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  • 1.
    Ahnström, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, Tommy
    Karolinska University Hospital.
    Skoog, Lambert
    Karolinska University Hospital.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer2009In: International Journal of Oncology, ISSN 1019-6439, Vol. 34, no 2, p. 441-448Article in journal (Refereed)
    Abstract [en]

    Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G(1) phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI, 0.24-0.72). Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.93) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).

  • 2.
    Antoniou, Antonis C.
    et al.
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Beesley, Jonathan
    Queensland Institute of Medical Research, Brisbane, Australia.
    McGuffog, Lesley
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    M. Sinilnikova, Olga
    Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, Lyon, France.
    Healey, Sue
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    L. Neuhausen, Susan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    Chun Ding, Yuan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    R. Rebbeck, Timothy
    University Penn, Sch Med, Abramson Canc Centre, Philadelphia, PA 19104 USA.
    N. Weitzel, Jeffrey
    City Hope Natl Med Centre, Duarte, CA 91010 USA.
    T. Lynch, Henry
    Creighton University, Omaha, NE 68178 USA.
    Isaacs, Claudine
    A. Ganz, Patricia
    University Calif Los Angeles, Jonsson Comprehens Canc Centre, Los Angeles, CA 90024 USA.
    Tomlinson, Gail
    University Texas Hlth Science Centre San Antonio, San Antonio, TX 78229 USA.
    I. Olopade, Olufunmilayo
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    J. Couch, Fergus
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    Wang, Xianshu
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    M. Lindor, Noralane
    Mayo Clin, Department Med Genet, Rochester, MN USA.
    S. Pankratz, Vernon
    Mayo Clin, Department Hlth Science Research, Rochester, MN USA.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Barile, Monica
    IEO, Div Canc Prevent and Genet, Milan, Italy.
    Viel, Alessandra
    IRCCS, CRO, Div Expt Oncol 1, Aviano, PN, Italy.
    Allavena, Anna
    University Turin, Department Genet Biol and Biochem, Turin, Italy.
    DallOlio, Valentina
    Cogentech, Consortium Genom Technology, Milan, Italy.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    I. Szabo, Csilla
    Mayo Clin, Coll Med, Department Lab Med and Pathol, Rochester, MN USA.
    Zikan, Michal
    Charles University Prague, Fac Med 1, Department Biochem and Expt Oncol, Prague, Czech Republic.
    Claes, Kathleen
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Poppe, Bruce
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Foretova, Lenka
    Masaryk Mem Canc Institute, Department Canc Epidemiol and Genet, Brno, Czech Republic.
    L. Mai, Phuong
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    H. Greene, Mark
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    Rennert, Gad
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Lejbkowicz, Flavio
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Glendon, Gord
    OCGN, Toronto, ON, Canada.
    Ozcelik, Hilmi
    Mt Sinai Hospital, Fred A Litwin Centre Canc Genet, Samuel Lunenfeld Research Institute, New York, NY 10029 USA.
    L. Andrulis, Irene
    OCGN, Toronto, ON, Canada.
    Thomassen, Mads
    Odense University Hospital, Department Clin Genet, DK-5000 Odense, Denmark.
    Gerdes, Anne-Marie
    Rigshosp, Department Clin Genet, Odense, Denmark.
    Sunde, Lone
    Aalborg Hospital, Department Clin Genet, Aalborg, Denmark.
    Cruger, Dorthe
    Vejle Hospital, Department Clin Genet, Velje, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Department Clin Genet, DK-8000 Aarhus, Denmark.
    Caligo, Maria
    University Pisa, Div Surg Mol and Ultrastruct Pathol, Department Oncol, Pisa, Italy.
    Friedman, Eitan
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Kaufman, Bella
    Sheba Med Centre, Institute Oncol, Tel Hashomer, Israel.
    Laitman, Yael
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Milgrom, Roni
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Dubrovsky, Maya
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Cohen, Shimrit
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Borg, Ake
    Lund University, Department Oncol, Lund, Sweden.
    Jernstroem, Helena
    Lund University, Department Oncol, Lund, Sweden.
    Lindblom, Annika
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Rantala, Johanna
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umea University, Department Radiat Science, Umea, Sweden.
    Nathanson, Kate
    University Penn, Philadelphia, PA 19104 USA.
    Domchek, Susan
    University Penn, Philadelphia, PA 19104 USA.
    Jakubowska, Ania
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Lubinski, Jan
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Huzarski, Tomasz
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Osorio, Ana
    Spanish Natl Canc Research Centre, Human Genet Grp, Human Canc Genet Programme, Madrid, Spain.
    Lasa, Adriana
    Hospital Santa Creu and Sant Pau, Genet Serv, Barcelona, Spain.
    Duran, Mercedes
    University Valladolid, Institute Biol and Mol Genet, IBGM UVA, Valladolid, Spain.
    Tejada, Maria-Isabel
    Cruces Hospital Barakaldo, Mol Genet Lab, Department Biochem, Bizkaia, Spain.
    Godino, Javier
    University Lozano Blesa, Hospital Clin, Oncol Serv, Zaragoza, Spain.
    Benitez, Javier
    Spanish Natl Canc Research Centre, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain.
    Hamann, Ute
    Deutsch Krebsforschungszentrum, Mol Genet Breast Canc, D-6900 Heidelberg, Germany.
    Kriege, Mieke
    Daniel Denhoed Canc Centre, Erasmus MC, Department Med Oncol, Family Canc Clin, Rotterdam, Netherlands.
    Hoogerbrugge, Nicoline
    Radboud University Nijmegen, Nijmegen Med Centre, Hereditary Canc Clin, NL-6525 ED Nijmegen, Netherlands.
    B. van der Luijt, Rob
    University Med Centre Utrecht, Department Med Genet, Utrecht, Netherlands.
    J. van Asperen, Christi
    Leiden University, Med Centre, Department Clin Genet, Leiden, Netherlands.
    Devilee, Peter
    Leiden University, Department Human Genet, Med Centre, Department Pathol, NL-2300 RA Leiden, Netherlands.
    J. Meijers-Heijboer, E.
    Vrije University Amsterdam Med Centre, Department Clin Genet, Amsterdam, Netherlands.
    J. Blok, Marinus
    University Med Centre, Department Genet and Cell Biol, Maastricht, Netherlands.
    M. Aalfs, Cora
    University Amsterdam, Acad Med Centre, Department Clin Genet, NL-1105 AZ Amsterdam, Netherlands.
    Hogervorst, Frans
    Netherlands Canc Institute, Family Canc Clin, Amsterdam, Netherlands.
    Rookus, Matti
    Netherlands Canc Institute, Department Epidemiol, Amsterdam, Netherlands.
    Cook, Margaret
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Oliver, Clare
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Frost, Debra
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Conroy, Don
    University Cambridge, Department Oncol, Cambridge, England.
    Gareth Evans, D.
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Lalloo, Fiona
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Pichert, Gabriella
    Guys and St Thomas NHS Fdn Trust, London, England.
    Davidson, Rosemarie
    Ferguson Smith Centre Clin Genet, Glasgow, Lanark, Scotland.
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands, England.
    Cook, Jackie
    Sheffield Childrens Hospital, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England.
    Paterson, Joan
    Addenbrookes Hospital, Department Clin Genet, E Anglian Reg Genet Serv, Cambridge, England.
    Hodgson, Shirley
    University London, Department Clin Genet, St Georges Hospital, London, England.
    J. Morrison, Patrick
    Belfast City Hospital, Northern Ireland Reg Genet Centre, Belfast BT9 7AD, Antrim, North Ireland.
    E. Porteous, Mary
    Western Gen Hospital, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland.
    Walker, Lisa
    Churchill Hospital, Oxford Reg Genet Serv, Oxford OX3 7LJ, England.
    John Kennedy, M.
    St James Hospital, Canc Genet Program, Hope Directorate, Dublin, Ireland.
    Dorkins, Huw
    Kennedy Galton Centre, NW Thames Reg Genet Serv, Harrow, Middx, England.
    Peock, Susan
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    K. Godwin, Andrew
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    Stoppa-Lyonnet, Dominique
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    de Pauw, Antoine
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    Mazoyer, Sylvie
    University Lyon 1, CNRS, Centre Leon Berard, Equipe Labellisee LIGUE 2008,UMR5201, F-69365 Lyon, France.
    Bonadona, Valerie
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Lasset, Christine
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Dreyfus, Helene
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Leroux, Dominique
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Hardouin, Agnes
    Centre Francois Baclesse, F-14021 Caen, France.
    Berthet, Pascaline
    Centre Francois Baclesse, F-14021 Caen, France.
    Faivre, Laurence
    Centre Hospital University Dijon, Centre Genet, Dijon, France.
    Loustalot, Catherine
    Centre Lutte Canc Georges Francois Leclerc, Dijon, France.
    Noguchi, Tetsuro
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Sobol, Hagay
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Rouleau, Etienne
    Centre Rene Huguenin, INSERM, U735, St Cloud, France.
    Nogues, Catherine
    Frenay, Marc
    Centre Antoine Lacassagne, F-06054 Nice, France.
    Venat-Bouvet, Laurence
    Centre Hospital University Limoges, Department Oncol, Limoges, France.
    L. Hopper, John
    University Melbourne, Melbourne, Vic, Australia.
    B. Daly, Mary
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    B. Terry, Mary
    Columbia University, New York, NY USA.
    M. John, Esther
    Canc Prevent Institute Calif, Fremont, CA USA.
    S. Buys, Saundra
    University Utah, Hlth Science Centre, Huntsman Canc Institute, Salt Lake City, UT USA.
    Yassin, Yosuf
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Miron, Alexander
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Goldgar, David
    University Utah, Department Dermatol, Salt Lake City, UT USA.
    F. Singer, Christian
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Catharina Dressler, Anne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Gschwantler-Kaulich, Daphne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Pfeiler, Georg
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    V. O. Hansen, Thomas
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    Jnson, Lars
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    A. Agnarsson, Bjarni
    University Hospital, Department Pathol, Reykjavik, Iceland.
    Kirchhoff, Tomas
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Offit, Kenneth
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Devlin, Vincent
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Dutra-Clarke, Ana
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Piedmonte, Marion
    Roswell Pk Canc Institute, GOG Stat and Data Centre, Buffalo, NY 14263 USA.
    C. Rodriguez, Gustavo
    NorthShore University Hlth Syst, Evanston NW Healthcare, Evanston, IL USA.
    Wakeley, Katie
    Tufts University, New England Med Centre, Boston, MA 02111 USA.
    F. Boggess, John
    University N Carolina, Chapel Hill, NC USA.
    Basil, Jack
    St Elizabeth Hospital, Edgewood, KY USA.
    E. Schwartz, Peter
    Yale University, Sch Med, New Haven, CT USA.
    V. Blank, Stephanie
    NYU, Sch Med, New York, NY USA.
    Ewart Toland, Amanda
    Ohio State University, Centre Comprehens Canc, Department Internal Med and Mol Virol, Div Human Canc Genet, Columbus, OH 43210 USA.
    Montagna, Marco
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Casella, Cinzia
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Imyanitov, Evgeny
    NN Petrov Institute Oncol, St Petersburg, Russia.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Riga, Latvia.
    Blanco, Ignacio
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    Lazaro, Conxi
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    J. Ramus, Susan
    University London Imperial Coll Science Technology and Med, Gynaecol Oncol Unit, UCL EGA Institute Womens Hlth, London, England.
    Sucheston, Lara
    Roswell Pk Canc Institute, Department Canc Prevent and Control, Buffalo, NY 14263 USA.
    Y. Karlan, Beth
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Gross, Jenny
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Schmutzler, Rita
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Wappenschmidt, Barbara
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Engel, Christoph
    University Leipzig, Institute Med Informat Stat and Epidemiol, Leipzig, Germany.
    Meindl, Alfons
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Lochmann, Magdalena
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Arnold, Norbert
    University Kiel, Department Obstet and Gynaecol, University Hospital Schleswig Holstein, Kiel, Germany.
    Heidemann, Simone
    University Kiel, Institute Human Genet, University Hospital Schleswig Holstein, Kiel, Germany.
    Varon-Mateeva, Raymonda
    Campus Virchow Klinikum, Charite Berlin, Institute Human Genet, Berlin, Germany.
    Niederacher, Dieter
    University Dusseldorf, Department Obstet and Gynaecol, Div Mol Genet, University Hospital Dusseldorf, Dusseldorf, Germany.
    Sutter, Christian
    University Heidelberg, Institute Human Genet, Div Mol Diagnost, Heidelberg, Germany.
    Deissler, Helmut
    University Hospital Ulm, Department Obstet and Gynaecol, Ulm, Germany.
    Gadzicki, Dorothea
    Hannover Med Sch, Institute Cell and Mol Pathol, D-3000 Hannover, Germany.
    Preisler-Adams, Sabine
    University Hospital Muenster, Institute Human Genet, Munster, Germany.
    Kast, Karin
    Tech University Dresden, Department Obstet and Gynaecol, University Hospital Carl Gustav Carus, Dresden, Germany.
    Schoenbuchner, Ines
    University Wurzburg, Institute Human Genet, Div Med Genet, Wurzburg, Germany.
    Caldes, Trinidad
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    de la Hoya, Miguel
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    Aittomaeki, Kristiina
    University Helsinki, Cent Hospital, Department Clin Genet, Helsinki, Finland.
    Nevanlinna, Heli
    University Helsinki, Cent Hospital, Department Obstet and Gynecol, FIN-00290 Helsinki, Finland.
    Simard, Jacques
    Centre Hospital University Quebec, Canada Research Chair Oncogenet, Canc Genom Lab, Quebec City, PQ, Canada.
    B. Spurdle, Amanda
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Holland, Helene
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Chen, Xiaoqing
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Platte, Radka
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Chenevix-Trench, Georgia
    Queensland Institute of Medical Research, Brisbane, Australia.
    F. Easton, Douglas
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.

  • 3.
    Arver, Brita
    et al.
    Karolinska Institute.
    Isaksson, Karin
    Karolinska Institute.
    Atterhem, Hans
    Umea University Hospital.
    Baan, Annika
    Sahlgrens University Hospital.
    Bergkvist, Leif
    Uppsala University.
    Brandberg, Yvonne
    Karolinska Institute.
    Ehrencrona, Hans
    Uppsala University.
    Emanuelsson, Monica
    Umea University.
    Hellborg, Henrik
    Karolinska University Hospital.
    Henriksson, Karin
    Skane University Hospital.
    Karlsson, Per
    Sahlgrens University Hospital.
    Loman, Niklas
    Skane University Hospital.
    Lundberg, Jonas
    Sahlgrens University Hospital.
    Ringberg, Anita
    Skane University Hospital.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Wickman, Marie
    Karolinska Institute.
    Sandelin, Kerstin
    Karolinska Institute.
    Bilateral Prophylactic Mastectomy in Swedish Women at High Risk of Breast Cancer: A National Survey2011In: ANNALS OF SURGERY, ISSN 0003-4932, Vol. 253, no 6, p. 1147-1154Article in journal (Refereed)
    Abstract [en]

    Background/Objective: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. Methods: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. Results: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low(3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1 unanticipated secondary operation.

  • 4.
    Bengtsson, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Joost, Patrick
    Lund University, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Off Medical Serv, Sweden; Lund University, Sweden.
    Backman, Ann-Sofie
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Melin, Beatrice
    Umeå University, Sweden.
    von Salome, Jenny
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Zagoras, Theofanis
    Sahlgrens University Hospital, Sweden.
    Gebre-Medhin, Samuel
    Lund University, Sweden; Karolinska University Hospital, Sweden.
    Burman, Pia
    Lund University, Sweden.
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 3928-3932Article in journal (Refereed)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 5.
    Blanco, Ignacio
    et al.
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Kuchenbaecker, Karoline
    University of Cambridge, England.
    Cuadras, Daniel
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Wang, Xianshu
    Mayo Clin, MN USA.
    Barrowdale, Daniel
    University of Cambridge, England.
    Ruiz de Garibay, Gorka
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Librado, Pablo
    University of Barcelona, Spain.
    Sanchez-Gracia, Alejandro
    University of Barcelona, Spain.
    Rozas, Julio
    University of Barcelona, Spain.
    Bonifaci, Nuria
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    McGuffog, Lesley
    University of Cambridge, England.
    Pankratz, Vernon S.
    Mayo Clin, MN USA.
    Islam, Abul
    University of Dhaka, Bangladesh.
    Mateo, Francesca
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Berenguer, Antoni
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Petit, Anna
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Catala, Isabel
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Brunet, Joan
    Hospital Josep Trueta, Spain.
    Feliubadalo, Lidia
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Tornero, Eva
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease, Spain.
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease, Spain.
    Cajal, Teresa Ramon Y.
    Hospital Santa Creu and Sant Pau, Spain.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Aittomaki, Kristiina
    University of Helsinki, Finland.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Toland, Amanda E.
    Ohio State University, OH 43210 USA.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Walsh, Christine
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Greene, Mark H.
    National Cancer Institute, MD USA.
    Mai, Phuong L.
    National Cancer Institute, MD USA.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA 94143 USA.
    Andrulis, Irene L.
    University of Toronto, Canada; University of Toronto, Canada; University of Toronto, Canada.
    Domchek, Susan M.
    University of Penn, PA 19104 USA; University of Penn, PA 19104 USA.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA; University of Penn, PA 19104 USA.
    Rebbeck, Timothy R.
    University of Penn Perelman, PA 19104 USA; University of Penn Perelman, PA 19104 USA.
    Barkardottir, Rosa B.
    University of Iceland, Iceland; University of Iceland, Iceland.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Durda, Katarzyna
    Pomeranian Medical University, Poland.
    Jaworska-Bieniek, Katarzyna
    Pomeranian Medical University, Poland.
    Claes, Kathleen
    University of Ghent, Belgium.
    Van Maerken, Tom
    University of Ghent, Belgium.
    Diez, Orland
    Vall Hebron Research Institute VHIR, Spain; University of Autonoma Barcelona, Spain.
    Hansen, Thomas V.
    Copenhagen University Hospital, Denmark.
    Jonson, Lars
    Copenhagen University Hospital, Denmark.
    Gerdes, Anne-Marie
    Copenhagen University Hospital, Denmark.
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark.
    de la Hoya, Miguel
    San Carlos Research Institute IdISSC, Spain.
    Caldes, Trinidad
    San Carlos Research Institute IdISSC, Spain.
    Dunning, Alison M.
    University of Cambridge, England.
    Oliver, Clare
    University of Cambridge, England.
    Fineberg, Elena
    University of Cambridge, England.
    Cook, Margaret
    University of Cambridge, England.
    Peock, Susan
    University of Cambridge, England.
    McCann, Emma
    Glan Clwyd Gen Hospital, Wales.
    Murray, Alex
    Singleton Hospital, Wales.
    Jacobs, Chris
    Guys and St Thomas National Health Serv NHS Fdn Trust, England.
    Pichert, Gabriella
    Guys and St Thomas National Health Serv NHS Fdn Trust, England.
    Lalloo, Fiona
    Central Manchester University Hospital National Health Serv NHS Fdn, England.
    Chu, Carol
    Yorkshire Regional Genet Serv, England.
    Dorkins, Huw
    Kennedy Galton Centre, England.
    Paterson, Joan
    Addenbrookes Hospital, England.
    Ong, Kai-Ren
    Birmingham Womens Hospital Healthcare National Health Serv, England.
    Teixeira, Manuel R.
    University of Porto, Portugal; University of Porto, Portugal.
    Teixeira,
    Netherlands Cancer Institute, The Netherlands.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, The Netherlands.
    van der Hout, Annemarie H.
    University of Groningen, Netherlands.
    Seynaeve, Caroline
    Erasmus University, Netherlands.
    van der Luijt, Rob B.
    University of Medical Centre Utrecht, Netherlands.
    Ligtenberg, Marjolijn J. L.
    Radboud University of Nijmegen, Netherlands; Radboud University of Nijmegen, Netherlands; Leiden University, Netherlands.
    Devilee, Peter
    Leiden University, Netherlands; Leiden University, Netherlands.
    Wijnen, Juul T.
    Leiden University, Netherlands; Leiden University, Netherlands.
    Rookus, Matti A.
    Netherlands Cancer Institute, Netherlands.
    Meijers-Heijboer, Hanne E. J.
    Vrije University of VJ University of Medical Centre, Netherlands.
    Blok, Marinus J.
    Maastricht University, Netherlands.
    van den Ouweland, Ans M. W.
    Erasmus University, Netherlands.
    Aalfs, Cora M.
    University of Amsterdam, Netherlands.
    Rodriguez, Gustavo C.
    University of Chicago, IL 60637 USA.
    Phillips, Kelly-Anne A.
    Peter MacCallum Cancer Centre, Australia.
    Piedmonte, Marion
    Roswell Pk Cancer Institute, NY 14263 USA.
    Nerenstone, Stacy R.
    Hartford Hospital, CT USA.
    Bae-Jump, Victoria L.
    University of N Carolina, NC USA.
    OMalley, David M.
    Ohio State University, OH USA.
    Ratner, Elena S.
    Yale University, CT USA.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Rhiem, Kerstin
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Engel, Christoph
    University of Leipzig, Germany.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Ditsch, Nina
    University of Munich, Germany.
    Arnold, Norbert
    University of Kiel, Germany.
    Plendl, Hansjoerg J.
    University of Kiel, Germany.
    Niederacher, Dieter
    University of Dusseldorf, Germany.
    Sutter, Christian
    University of Heidelberg Hospital, Germany.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Steinemann, Doris
    Hannover Medical Sch, Germany.
    Preisler-Adams, Sabine
    University of Munster, Germany.
    Kast, Karin
    Technical University of Dresden, Germany.
    Varon-Mateeva, Raymonda
    Charite, Germany.
    Gehrig, Andrea
    University of Wurzburg, Germany.
    Bojesen, Anders
    Vejle Hospital, Denmark.
    Sokilde Pedersen, Inge
    Aalborg University Hospital, Denmark.
    Sunde, Lone
    Aarhus University Hospital, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Kruse, Torben A.
    Odense University Hospital, Denmark.
    Foretova, Lenka
    Masaryk Mem Cancer Institute, Czech Republic.
    Peterlongo, Paolo
    Fdn Italiana Ric Cancro, Italy.
    Bernard, Loris
    Cogentech Cancer Genet Test Lab, Italy.
    Peissel, Bernard
    Fdn Ist Nazl Tumori INT, Italy.
    Scuvera, Giulietta
    Fdn Ist Nazl Tumori INT, Italy.
    Manoukian, Siranoush
    Fdn Ist Nazl Tumori INT, Italy.
    Radice, Paolo
    Fdn Ist Nazl Tumori INT, Italy.
    Ottini, Laura
    University of Roma La Sapienza, Italy.
    Montagna, Marco
    IRCCS, Italy.
    Agata, Simona
    IRCCS, Italy.
    Maugard, Christine
    Hop University of Strasbourg, France.
    Simard, Jacques
    Centre Hospital University of Quebec, Canada; University of Laval, Canada.
    Soucy, Penny
    Centre Hospital University of Quebec, Canada; University of Laval, Canada.
    Berger, Andreas
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Fink-Retter, Anneliese
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Singer, Christian F.
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Rappaport, Christine
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Geschwantler-Kaulich, Daphne
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Tea, Muy-Kheng
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Pfeiler, Georg
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    John, Esther M.
    Cancer Prevent Institute Calif, CA USA.
    Miron, Alex
    Dana Farber Cancer Institute, MA 02115 USA.
    Neuhausen, Susan L.
    Beckman Research Institute City Hope, CA USA.
    Beth Terry, Mary
    Columbia University, NY USA.
    Chung, Wendy K.
    Columbia University, NY USA.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Goldgar, David E.
    University of Utah, UT USA.
    Janavicius, Ramunas
    Vilnius University, Lithuania.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    van Rensburg, Elisabeth J.
    University of Pretoria, South Africa.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Konstantopoulou, Irene
    National Centre Science Research Demokritos, Greece.
    Garber, Judy
    Harvard University, MA USA.
    Godwin, Andrew K.
    University of Kansas, KS 66103 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Narod, Steven A.
    University of Toronto, Canada.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel; B Rappaport Fac Med, Israel.
    Shimon Paluch, Shani
    Chaim Sheba Medical Centre, Israel.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel; Tel Aviv University, Israel.
    Liljegren, Annelie
    Karolinska University Hospital, Sweden.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Loman, Niklas
    University of Lund Hospital, Sweden.
    Imyanitov, Evgeny N.
    NN Petrov Institute Oncol, Russia.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Spurdle, Amanda B.
    Queensland Institute Medical Research, Australia.
    Healey, Sue
    Queensland Institute Medical Research, Australia.
    Weitzel, Jeffrey N.
    City Hope National Medical Centre, CA USA.
    Herzog, Josef
    City Hope National Medical Centre, CA USA.
    Margileth, David
    Care City Hope Clin Cancer Genet Commun Research Network, CA USA.
    Gorrini, Chiara
    University of Health Network, Canada.
    Esteller, Manel
    IDIBELL, Spain; University of Barcelona, Spain; Catalan Institute Research and Adv Studies ICREA, Spain.
    Gomez, Antonio
    IDIBELL, Spain.
    Sayols, Sergi
    IDIBELL, Spain.
    Vidal, Enrique
    IDIBELL, Spain.
    Heyn, Holger
    IDIBELL, Spain.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; Institute Curie, France; University of Paris 05, France.
    Leone, Melanie
    Hospital Civils Lyon, France.
    Barjhoux, Laure
    University of Lyon 1, France.
    Fassy-Colcombet, Marion
    Institute Curie, France.
    de Pauw, Antoine
    Institute Curie, France.
    Lasset, Christine
    University of Lyon 1, France; Centre Leon Berard, France.
    Fert Ferrer, Sandra
    Hop Hotel Dieu, France.
    Castera, Laurent
    Institute Curie, France.
    Berthet, Pascaline
    Centre Francois Baclesse, France.
    Cornelis, Francois
    Avicenne Hospital, France; Sud Francilien Hospital, France; University Hospital, France.
    Bignon, Yves-Jean
    University of Clermont Ferrand, France.
    Damiola, Francesca
    University of Lyon 1, France.
    Mazoyer, Sylvie
    University of Lyon 1, France.
    Sinilnikova, Olga M.
    Hospital Civils Lyon, France; University of Lyon 1, France.
    Maxwell, Christopher A.
    University of British Columbia, Canada.
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Kauff, Noah
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Corines, Marina J.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Villano, Danylko
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Cunningham, Julie
    Mayo Clin, MN USA; Mayo Clin, MN USA.
    Lee, Adam
    Mayo Clin, MN USA.
    Lindor, Noralane
    Mayo Clin Scottsdale, AZ USA.
    Lazaro, Conxi
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Easton, Douglas F.
    University of Cambridge, England.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research, Australia.
    Couch, Fergus J.
    Mayo Clin, MN USA; Mayo Clin, MN USA.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Angel Pujana, Miguel
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0120020Article in journal (Refereed)
    Abstract [en]

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values greater than 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  • 6.
    Couch, Fergus J.
    et al.
    Mayo Clin, MN 55905 USA; Mayo Clin, MN 55905 USA.
    Kuchenbaecker, Karoline B.
    University of Cambridge, England.
    Michailidou, Kyriaki
    University of Cambridge, England.
    Mendoza-Fandino, Gustavo A.
    University of S Florida, FL 33612 USA.
    Nord, Silje
    Radiumhosp, Norway.
    Lilyquist, Janna
    Mayo Clin, MN 55905 USA.
    Olswold, Curtis
    Mayo Clin, MN 55905 USA.
    Hallberg, Emily
    Mayo Clin, MN 55905 USA.
    Agata, Simona
    IRCCS, Italy.
    Ahsan, Habibul
    University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA.
    Aittomaeki, Kristiina
    University of Helsinki, Finland.
    Ambrosone, Christine
    Roswell Pk Cancer Institute, NY 14263 USA.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; University of Toronto, Canada.
    Anton-Culver, Hoda
    University of Calif Irvine, CA 92697 USA.
    Arndt, Volker
    German Cancer Research Centre, Germany.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Barkardottir, Rosa B.
    Landspitali University Hospital, Iceland; University of Iceland, Iceland.
    Barrowdale, Daniel
    University of Cambridge, England.
    Beckmann, Lars
    Institute Qual and Efficiency Health Care IQWiG, Germany.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain; Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease CIBERER, Spain.
    Blank, Stephanie V.
    NYU, NY 10016 USA.
    Blomqvist, Carl
    University of Helsinki, Finland; University of Helsinki, Finland.
    Bogdanova, Natalia V.
    Hannover Medical Sch, Germany.
    Bojesen, Stig E.
    Copenhagen University Hospital, Denmark.
    Bolla, Manjeet K.
    University of Cambridge, England.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University of Tubingen, Germany.
    Brenner, Hermann
    German Cancer Research Centre, Germany; German Cancer Research Centre, Germany; National Centre Tumor Disease NCT, Germany.
    Burwinkel, Barbara
    Heidelberg University, Germany.
    Buys, Saundra S.
    University of Utah, UT 84112 USA.
    Caldes, Trinidad
    IdISSC, Spain.
    Caligo, Maria A.
    University of Pisa, Italy; University Hospital Pisa, Italy.
    Canzian, Federico
    German Cancer Research Centre, Germany.
    Carpenter, Jane
    University of Sydney, Australia.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany.
    Chanock, Stephen J.
    NCI, MD 20850 USA.
    Chung, Wendy K.
    Columbia University, NY 10032 USA; Columbia University, NY 10032 USA.
    Claes, Kathleen B. M.
    University of Ghent, Belgium.
    Cox, Angela
    University of Sheffield, England.
    Cross, Simon S.
    University of Sheffield, England.
    Cunningham, Julie M.
    Mayo Clin, MN 55905 USA.
    Czene, Kamila
    Karolinska Institute, Sweden.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Damiola, Francesca
    University of Lyon, France.
    Darabi, Hatef
    Karolinska Institute, Sweden.
    de la Hoya, Miguel
    IdISSC, Spain.
    Devilee, Peter
    Leiden University, Netherlands.
    Diez, Orland
    University Hospital Vall dHebron, Spain; University of Autonoma Barcelona, Spain.
    Ding, Yuan C.
    City Hope National Medical Centre, CA 91010 USA.
    Dolcetti, Riccardo
    CRO Aviano National Cancer Institute, Italy.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    dos-Santos-Silva, Isabel
    University of London London School Hyg and Trop Med, England.
    Dumont, Martine
    Centre Hospital University of Quebec, Canada; University of Laval, Canada.
    Dunning, Alison M.
    University of Cambridge, England.
    Eccles, Diana M.
    University of Southampton, England.
    Ehrencrona, Hans
    Uppsala University, Sweden; University of Lund Hospital, Sweden.
    Ekici, Arif B.
    University of Erlangen Nurnberg, Germany; Comprehens Cancer Centre EMN, Germany.
    Eliassen, Heather
    Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Ellis, Steve
    University of Cambridge, England.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany.
    Figueroa, Jonine
    NCI, MD 20850 USA.
    Flesch-Janys, Dieter
    University of Clin Hamburg Eppendorf, Germany; University of Clin Hamburg Eppendorf, Germany.
    Foersti, Asta
    German Cancer Research Centre, Germany; Lund University, Sweden.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Foulkes, William D.
    McGill University, Canada.
    Friebel, Tara
    University of Philadelphia, PA 19104 USA.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Frost, Debra
    University of Cambridge, England.
    Gabrielson, Marike
    Karolinska Institute, Sweden.
    Gammon, Marilie D.
    University of N Carolina, NC 27599 USA.
    Ganz, Patricia A.
    Jonsson Comprehens Cancer Centre, CA 90095 USA; Jonsson Comprehens Cancer Centre, CA 90095 USA.
    Gapstur, Susan M.
    Amer Cancer Soc, GA 30303 USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA 02215 USA.
    Gaudet, Mia M.
    Amer Cancer Soc, GA 30303 USA.
    Gayther, Simon A.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Gerdes, Anne-Marie
    Copenhagen University Hospital, Denmark.
    Ghoussaini, Maya
    University of Cambridge, England.
    Giles, Graham G.
    Cancer Council Victoria, Australia.
    Glendon, Gord
    Mt Sinai Hospital, Canada.
    Godwin, Andrew K.
    University of Kansas, KS 66205 USA.
    Goldberg, Mark S.
    McGill University, Canada; McGill University, Canada.
    Goldgar, David E.
    University of Utah, UT 84132 USA.
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre CNIO, Spain.
    Greene, Mark H.
    NCI, MD 20850 USA.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Guenel, Pascal
    CESP Centre Research Epidemiol and Populat Heatlh, France.
    Gunter, Marc
    University of London Imperial Coll Science Technology and Med, England.
    Haeberle, Lothar
    University of Erlangen Nurnberg, Germany.
    Haiman, Christopher A.
    University of So Calif, CA 90033 USA.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Hart, Steven
    Mayo Clin, MN 55905 USA.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Heikkinen, Tuomas
    Heidelberg University, Germany; University of Helsinki, Finland.
    Henderson, Brian E.
    University of So Calif, CA 90033 USA.
    Herzog, Josef
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Hollestelle, Antoinette
    Erasmus MC Cancer Institute, Netherlands.
    Hooning, Maartje J.
    Erasmus University, Netherlands.
    Hoover, Robert N.
    NCI, MD 20850 USA.
    Hopper, John L.
    University of Melbourne, Australia.
    Humphreys, Keith
    Karolinska Institute, Sweden.
    Hunter, David J.
    Harvard University, MA 02115 USA.
    Huzarski, Tomasz
    Pomeranian Medical University, Poland.
    Imyanitov, Evgeny N.
    NN Petrov Oncology Research Institute, Russia.
    Isaacs, Claudine
    Georgetown University, DC 20007 USA.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    James, Paul
    Peter MacCallum Cancer Centre, Australia; University of Melbourne, Australia.
    Janavicius, Ramunas
    State Research Institute, Lithuania.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    John, Esther M.
    Cancer Prevent Institute Calif, CA 94538 USA.
    Jones, Michael
    Institute Cancer Research, England.
    Kabisch, Maria
    German Cancer Research Centre, Germany.
    Kar, Siddhartha
    University of Cambridge, England.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Khan, Sofia
    University of Helsinki, Finland; University of Helsinki, Finland.
    Khaw, Kay-Tee
    University of Cambridge, England.
    Kibriya, Muhammad G.
    University of Chicago, IL 60637 USA.
    Knight, Julia A.
    Mt Sinai Hospital, Canada.
    Ko, Yon-Dschun
    Evangel Kliniken Bonn gGmbH, Germany.
    Konstantopoulou, Irene
    National Centre Science Research Demokritos, Greece.
    Kosma, Veli-Matti
    University of Eastern Finland, Finland.
    Kristensen, Vessela
    Radiumhosp, Norway.
    Kwong, Ava
    Hong Kong Hereditary Breast Cancer Family Registry, Peoples R China; University of Hong Kong, Peoples R China.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Lambrechts, Diether
    VIB, Belgium.
    Lazaro, Conxi
    IDIBELL Catalan Institute Oncol, Spain.
    Lee, Eunjung
    University of So Calif, CA 90032 USA.
    Le Marchand, Loic
    University of Cancer Centre, HI 96813 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lindblom, Annika
    Karolinska Institute, Sweden.
    Lindor, Noralane
    Mayo Clin, AZ 85259 USA.
    Lindstrom, Sara
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Liu, Jianjun
    Genome Institute Singapore, Singapore.
    Long, Jirong
    Vanderbilt University, TN 37203 USA; Vanderbilt University, TN 37203 USA.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Mai, Phuong L.
    NCI, MD 20850 USA.
    Makalic, Enes
    University of Melbourne, Australia.
    Malone, Kathleen E.
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98195 USA.
    Mannermaa, Arto
    University of Eastern Finland, Finland.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Margolin, Sara
    Karolinska University Hospital, Sweden.
    Marme, Frederik
    Heidelberg University, Germany.
    Martens, John W. M.
    Erasmus MC Cancer Institute, Netherlands.
    McGuffog, Lesley
    University of Cambridge, England.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Miller, Austin
    Roswell Pk Cancer Institute, NY 14263 USA.
    Milne, Roger L.
    Cancer Council Victoria, Australia.
    Miron, Penelope
    Case Western Reserve University, OH 44106 USA.
    Montagna, Marco
    IRCCS, Italy.
    Mazoyer, Sylvie
    University of Lyon, France.
    Mulligan, Anna M.
    University of Health Network, Canada; University of Toronto, Canada.
    Muranen, Taru A.
    Heidelberg University, Germany; University of Helsinki, Finland.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Neuhausen, Susan L.
    City Hope National Medical Centre, CA 91010 USA.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Nordestgaard, Borge G.
    Copenhagen University Hospital, Denmark.
    Nussbaum, Robert L.
    Invitae Corp, CA 94107 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Olson, Janet E.
    Mayo Clin, MN 55905 USA.
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain.
    Park, Sue K.
    Seoul National University, South Korea; Seoul National University, South Korea.
    Peeters, Petra H.
    University of Medical Centre, Netherlands; University of London Imperial Coll Science Technology and Med, England.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Peterlongo, Paolo
    Fdn Ist FIRC Oncology Mol, Italy.
    Peto, Julian
    University of London London School Hyg and Trop Med, England.
    Phelan, Catherine M.
    University of S Florida, FL 33612 USA.
    Pilarski, Robert
    Ohio State University, OH 43210 USA.
    Poppe, Bruce
    University of Ghent, Belgium.
    Pylkaes, Katri
    University of Oulu, Finland; University of Oulu, Finland; University of Oulu, Finland.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Rahman, Nazneen
    Institute Cancer Research, England.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Rappaport, Christine
    Medical University of Vienna, Austria.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel; B Rappaport Fac Med, Israel.
    Richardson, Andrea
    Johns Hopkins University, MD 21205 USA.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Romieu, Isabelle
    Int Agency Research Canc, France.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Rutgers, Emiel J.
    Antoni van Leeuwenhoek Hospital, Netherlands.
    Sanchez, Maria-Jose
    University of Granada, Spain; CIBER Epidemiol and Salud Public CIBERESP, Spain.
    Santella, Regina M.
    Columbia University, NY 10032 USA.
    Sawyer, Elinor J.
    Kings Coll London, England.
    Schmidt, Daniel F.
    University of Melbourne, Australia.
    Schmidt, Marjanka K.
    Antoni van Leeuwenhoek Hospital, Netherlands.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Schumacher, Fredrick
    University of So Calif, CA 90033 USA.
    Scott, Rodney
    John Hunter Hospital, Australia.
    Senter, Leigha
    Ohio State University, OH 43210 USA.
    Sharma, Priyanka
    University of Kansas, KS 66205 USA.
    Simard, Jacques
    University of Laval, Canada.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Sinilnikova, Olga M.
    University of Lyon, France; Hospital Civils Lyon, France.
    Soucy, Penny
    University of Laval, Canada.
    Southey, Melissa
    University of Melbourne, Australia.
    Steinemann, Doris
    Hannover Medical Sch, Germany.
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; University of Paris 05, France.
    Swerdlow, Anthony
    Institute Cancer Research, England.
    Szabo, Csilla I.
    NHGRI, MD 20892 USA.
    Tamimi, Rulla
    Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Tapper, William
    University of Southampton, England.
    Teixeira, Manuel R.
    Portuguese Oncology Institute, Portugal; University of Porto, Portugal.
    Teo, Soo-Hwang
    Cancer Research Initiat Fdn, Malaysia; University of Malaya, Malaysia.
    Terry, Mary B.
    Columbia University, NY 10032 USA.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Thompson, Deborah
    University of Cambridge, England.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Toland, Amanda E.
    Ohio State University, OH 43210 USA.
    Tollenaar, Robert A. E. M.
    Leiden University, Netherlands.
    Tomlinson, Ian
    University of Oxford, England; University of Oxford, England.
    Truong, Therese
    CESP Centre Research Epidemiol and Populat Heatlh, France.
    Tsimiklis, Helen
    University of Melbourne, Australia.
    Teule, Alex
    IDIBELL Catalan Institute Oncol, Spain.
    Tumino, Rosario
    Civ MP Arezzo Hospital, Italy; Civ MP Arezzo Hospital, Italy.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Turnbull, Clare
    Institute Cancer Research, England.
    Ursin, Giski
    Institute Populat Based Cancer Research, Norway.
    van Deurzen, Carolien H. M.
    Erasmus University, Netherlands.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Varon-Mateeva, Raymonda
    Charite, Germany.
    Wang, Zhaoming
    NCI, MD 20877 USA.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Weiderpass, Elisabete
    Karolinska Institute, Sweden; Institute Populat Based Cancer Research, Norway; University of Tromso, Norway; Folkhalsan Research Centre, Finland.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Whittemore, Alice
    Stanford University, CA 94305 USA.
    Wildiers, Hans
    University Hospital, Belgium.
    Winqvist, Robert
    University of Oulu, Finland; University of Oulu, Finland; University of Oulu, Finland.
    Yang, Xiaohong R.
    NCI, MD 20892 USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece.
    Yao, Song
    Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
    Pilar Zamora, M.
    Hospital University of La Paz, Spain.
    Zheng, Wei
    Vanderbilt University, TN 37203 USA; Vanderbilt University, TN 37203 USA.
    Hall, Per
    Karolinska Institute, Sweden.
    Kraft, Peter
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Vachon, Celine
    Mayo Clin, MN 55905 USA.
    Slager, Susan
    Mayo Clin, MN 55905 USA.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Pharoah, Paul D. P.
    University of Cambridge, England.
    Monteiro, Alvaro A. N.
    University of S Florida, FL 33612 USA.
    Garcia-Closas, Montserrat
    NCI, MD 20850 USA.
    Easton, Douglas F.
    University of Cambridge, England.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, no 11375, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

  • 7.
    Couch, Fergus J.
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    Mayo Clin, MN USA.
    Wang, Xianshu
    Mayo Clin, MN USA.
    McGuffog, Lesley
    University of Cambridge, England.
    Lee, Andrew
    University of Cambridge, England Mayo Clin, MN USA.
    Olswold, Curtis
    Mayo Clin, MN USA.
    Kuchenbaecker, Karoline B.
    University of Cambridge, England.
    Soucy, Penny
    Centre Hospital University of Quebec, Canada University of Laval, Canada.
    Fredericksen, Zachary
    Mayo Clin, MN USA.
    Barrowdale, Daniel
    University of Cambridge, England.
    Dennis, Joe
    University of Cambridge, England.
    Gaudet, Mia M.
    Amer Cancer Soc, GA USA.
    Dicks, Ed
    University of Cambridge, England.
    Kosel, Matthew
    Mayo Clin, MN USA.
    Healey, Sue
    Queensland Institute Medical Research, Australia.
    Sinilnikova, Olga M.
    Hospital Civils Lyon, France University of Lyon 1, France.
    Lee, Adam
    University of Cambridge, England Mayo Clin, MN USA.
    Bacot, Francois
    Centre Innovat Genome Quebec, Canada McGill University, Canada.
    Vincent, Daniel
    Centre Innovat Genome Quebec, Canada McGill University, Canada.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Peock, Susan
    University of Cambridge, England.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France University of Paris 05, France.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy.
    Schmutzler, Rita Katharina
    University Hospital Cologne, Germany.
    Domchek, Susan M.
    University of Penn, PA USA.
    Piedmonte, Marion
    Roswell Pk Cancer Institute, NY USA.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Neuhausen, Susan L.
    City Hope National Medical Centre, CA USA.
    Szabo, Csilla I.
    University of Delaware, DE USA.
    Blanco, Ignacio
    IDIBELL Catalan Institute Oncol, Spain.
    Greene, Mark H.
    NCI, MD USA.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA USA.
    Phelan, Catherine M.
    University of S Florida, FL USA.
    Weitzel, Jeffrey N.
    City Hope National Medical Centre, CA USA.
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS, Italy.
    Olah, Edith
    National Institute Oncol, Hungary.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada.
    Godwin, Andrew K.
    University of Kansas, KS USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece .
    Goldgar, David E.
    University of Utah, UT USA .
    Caldes, Trinidad
    Hospital Clin San Carlos, Spain .
    Nevanlinna, Heli
    University of Helsinki, Finland .
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain Biomed Network Rare Disease CIBERER, Spain .
    Terry, Mary Beth
    Columbia University, NY USA .
    Daly, Mary B.
    Fox Chase Cancer Centre, PA USA .
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Ramus, Susan J.
    University of So Calif, CA USA .
    Ewart Toland, Amanda
    Ohio State University, OH USA .
    Caligo, Maria A.
    University of Pisa, Italy.
    Olopade, Olufunmilayo I.
    University of Chicago, IL USA .
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA USA .
    Claes, Kathleen
    Ghent University Hospital, Belgium .
    Beattie, Mary S.
    University of Calif San Francisco, CA USA .
    Southey, Melissa C.
    University of Melbourne, Australia .
    Imyanitov, Evgeny N.
    NN Petrov Oncology Research Institute, Russia .
    Tischkowitz, Marc
    McGill University, Canada .
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin, Lithuania .
    John, Esther M.
    Cancer Prevent Institute Calif, CA USA .
    Kwong, Ava
    Hong Kong Sanat and Hospital, Peoples R China .
    Diez, Orland
    University Hospital Vall dHebron, Spain Vall dHebron Institute Oncology VHIO, Spain .
    Balmana, Judith
    University Hospital, Spain .
    Barkardottir, Rosa B.
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX USA .
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel Carmel Hospital, Israel B Rappaport Fac Med, Israel .
    Teo, Soo-Hwang
    University of Malaya, Malaysia .
    Ganz, Patricia A.
    University of Calif Los Angeles, CA USA .
    Campbell, Ian
    Peter MacCallum Cancer Centre, Australia .
    van der Hout, Annemarie H.
    University of Groningen, Netherlands .
    van Deurzen, Carolien H. M.
    Erasmus University, Netherlands .
    Seynaeve, Caroline
    Erasmus University, Netherlands .
    Gomez Garcia, Encarna B.
    MUMC, Netherlands .
    van Leeuwen, Flora E.
    Netherlands Cancer Institute, Netherlands .
    Meijers-Heijboer, Hanne E. J.
    Vrije University of Amsterdam Medical Centre, Netherlands .
    Gille, Johannes
    Vrije University of Amsterdam Medical Centre, Netherlands .
    Ausems, Margreet G. E. M.
    University of Medical Centre Utrecht, Netherlands .
    Blok, Marinus J.
    Maastricht University of Medical Centre, Netherlands .
    Ligtenberg, Marjolijn J. L.
    Radboud University of Nijmegen, Netherlands.
    Rookus, Matti A.
    Netherlands Cancer Institute, Netherlands .
    Devilee, Peter
    Leiden University, Netherlands .
    Verhoef, Senno
    Netherlands Cancer Institute, Netherlands .
    van Os, Theo A. M.
    University of Amsterdam, Netherlands .
    Wijnen, Juul T.
    Leiden University, Netherlands .
    Frost, Debra
    University of Cambridge, England .
    Ellis, Steve
    University of Cambridge, UK.
    Fineberg, Elena
    University of Cambridge, England .
    Platte, Radka
    University of Cambridge, England .
    Evans, Gareth D.
    Central Manchester University Hospital NHS Fdn Trust, England .
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust, England .
    Eeles, Rosalind A.
    Institute Cancer Research, England Royal Marsden NHS Fdn Trust, England .
    Adlard, Julian
    Yorkshire Regional Genet Serv, England .
    Eccles, Diana M.
    University of Southampton, England .
    Cook, Jackie
    Sheffield Childrens Hospital, England .
    Brewer, Carole
    Royal Devon and Exeter Hospital, England .
    Douglas, Fiona
    Newcastle Upon Tyne Hospital NHS Trust, England .
    Hodgson, Shirley
    St Georges University of London, England .
    Morrison, Patrick J.
    Belfast Health and Social Care Trust, North Ireland Queens University of Belfast, North Ireland .
    Side, Lucy E.
    Great Ormond St Hospital Sick Children, England UCL, England .
    Donaldson, Alan
    St Michaels Hospital, England .
    Houghton, Catherine
    Liverpool Womens NHS Fdn Trust, England .
    Rogers, Mark T.
    University of Wales Hospital, Wales .
    Dorkins, Huw
    Kennedy Galton Centre, England .
    Eason, Jacqueline
    Nottingham University Hospital NHS Trust, England .
    Gregory, Helen
    NHS Grampian, Scotland University of Aberdeen, Scotland .
    McCann, Emma
    Glan Clwyd Hospital, Rhyl, UK.
    Murray, Alex
    Singleton Hospital, Wales .
    Calender, Alain
    Hospital Civils Lyon, France .
    Hardouin, Agnes
    Centre Francois Baclesse, France .
    Berthet, Pascaline
    Centre Francois Baclesse, France .
    Delnatte, Capucine
    Centre Rene Gauducheau, France .
    Nogues, Catherine
    Hop Rene Huguenin, France .
    Lasset, Christine
    Centre Leon Berard, France University of Lyon 1, France .
    Houdayer, Claude
    Institute Curie, France University of Paris 05, France .
    Leroux, Dominique
    CHU Grenoble, France University of Grenoble, France .
    Rouleau, Etienne
    Hop Rene Huguenin, France .
    Prieur, Fabienne
    Centre Hospital University of St Etienne, France .
    Damiola, Francesca
    University of Lyon 1, France .
    Sobol, Hagay
    University of Aix Marseille 2, France .
    Coupier, Isabelle
    CHU Arnaud de Villeneuve, France CRLCC Val dAurelle, France .
    Venat-Bouvet, Laurence
    Centre Hospital University of Dupuytren, France .
    Castera, Laurent
    Institute Curie, France .
    Gauthier-Villars, Marion
    Institute Curie, France .
    Leone, Melanie
    Hospital Civils Lyon, France .
    Pujol, Pascal
    CHU Arnaud de Villeneuve, France CRCM Val dAurelle, France .
    Mazoyer, Sylvie
    University of Lyon 1, France .
    Bignon, Yves-Jean
    University of Clermont Ferrand, France .
    Zlowocka-Perlowska, Elzbieta
    Pomeranian Medical University, Poland .
    Gronwald, Jacek
    Pomeranian Medical University, Poland .
    Lubinski, Jan
    Pomeranian Medical University, Poland .
    Durda, Katarzyna
    Pomeranian Medical University, Poland .
    Jaworska, Katarzyna
    Pomeranian Medical University, Poland Warsaw Medical University, Poland .
    Huzarski, Tomasz
    Pomeranian Medical University, Poland .
    Spurdle, Amanda B.
    Queensland Institute Medical Research, Australia .
    Viel, Alessandra
    IRCCS, Italy .
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Italy .
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy .
    Melloni, Giulia
    Fdn IRCCS Ist Nazl Tumori INT, Italy .
    Ottini, Laura
    University of Roma La Sapienza, Italy .
    Papi, Laura
    University of Florence, Italy .
    Varesco, Liliana
    IRCCS AOU San Martino IST Ist Nazl Ric Canc, Italy .
    Grazia Tibiletti, Maria
    Osped Circolo University of Insubria, Italy .
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Volorio, Sara
    Fdn Ist FIRC Oncology Mol, Italy Cogentech Cancer Genet Test Lab, Italy .
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Italy .
    Pensotti, Valeria
    Fdn Ist FIRC Oncology Mol, Italy Cogentech Cancer Genet Test Lab, Italy .
    Arnold, Norbert
    University of Kiel, Germany .
    Engel, Christoph
    University of Leipzig, Germany .
    Deissler, Helmut
    University Hospital Ulm, Germany .
    Gadzicki, Dorothea
    Hannover Medical Sch, Germany .
    Gehrig, Andrea
    University of Wurzburg, Germany .
    Kast, Karin
    Technical University of Dresden, Germany .
    Rhiem, Kerstin
    University Hospital Cologne, Germany .
    Meindl, Alfons
    Technical University of Munich, Germany .
    Niederacher, Dieter
    University of Dusseldorf, Germany .
    Ditsch, Nina
    University of Munich, Germany .
    Plendl, Hansjoerg
    University of Kiel, Germany .
    Preisler-Adams, Sabine
    University of Munster, Germany .
    Engert, Stefanie
    Technical University of Munich, Germany .
    Sutter, Christian
    Heidelberg University, Germany .
    Varon-Mateeva, Raymonda
    Institute Medical and Human Genet, Germany .
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany.
    Weber, Bernhard H. F.
    University of Regensburg, Germany .
    Arver, Brita
    Karolinska University Hospital, Sweden .
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Loman, Niklas
    University of Lund Hospital, Sweden .
    Rosenquist, Richard
    Uppsala University, Sweden .
    Einbeigi, Zakaria
    Sahlgrens University Hospital, Sweden .
    Nathanson, Katherine L.
    University of Penn, PA USA .
    Rebbeck, Timothy R.
    University of Penn, PA USA .
    Blank, Stephanie V.
    NYU, NY USA .
    Cohn, David E.
    Ohio State University, OH USA .
    Rodriguez, Gustavo C.
    University of Chicago, IL USA .
    Small, Laurie
    Maine Womens Surg and Cancer Centre, ME USA .
    Friedlander, Michael
    Australia New Zealand GOG, Australia .
    Bae-Jump, Victoria L.
    University of N Carolina, NC USA .
    Fink-Retter, Anneliese
    Medical University of Vienna, Austria .
    Rappaport, Christine
    Medical University of Vienna, Austria.
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna, Austria .
    Pfeiler, Georg
    Medical University of Vienna, Austria.
    Tea, Muy-Kheng
    Medical University of Vienna, Austria .
    Lindor, Noralane M.
    Mayo Clin Arizona, AZ USA .
    Kaufman, Bella
    Chaim Sheba Medical Centre, Israel .
    Shimon Paluch, Shani
    Chaim Sheba Medical Centre, Israel .
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel .
    Skytte, Anne-Bine
    Vejle Hospital, Denmark .
    Gerdes, Anne-Marie
    Rigshosp, Denmark .
    Sokilde Pedersen, Inge
    Aalborg University Hospital, Denmark .
    Traasdahl Moeller, Sanne
    Odense University Hospital, Denmark .
    Kruse, Torben A.
    Odense University Hospital, Denmark .
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark .
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY USA .
    Sarrel, Kara
    Mem Sloan Kettering Cancer Centre, NY USA .
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY USA .
    Kauff, Noah
    Mem Sloan Kettering Cancer Centre, NY USA .
    Mulligan, Anna Marie
    University of Toronto, Canada St Michaels Hospital, Canada.
    Glendon, Gord
    Mt Sinai Hospital, Canada .
    Ozcelik, Hilmi
    Mt Sinai Hospital, Canada University of Toronto, Canada .
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark .
    Nielsen, Finn C.
    Copenhagen University Hospital, Denmark .
    Jonson, Lars
    Copenhagen University Hospital, Denmark .
    Andersen, Mette K.
    Copenhagen University Hospital, Denmark .
    Chun Ding, Yuan
    City Hope National Medical Centre, CA USA .
    Steele, Linda
    City Hope National Medical Centre, CA USA .
    Foretova, Lenka
    Masaryk Mem Cancer Institute, Czech Republic .
    Teule, Alex
    IDIBELL Catalan Institute Oncol, Spain .
    Lazaro, Conxi
    IDIBELL Catalan Institute Oncol, Spain .
    Brunet, Joan
    IDIBGI Catalan Institute Oncol, Spain .
    Angel Pujana, Miquel
    IDIBELL Catalan Institute Oncol, Spain .
    Mai, Phuong L.
    NCI, MD USA .
    Loud, Jennifer T.
    NCI, MD USA .
    Walsh, Christine
    Cedars Sinai Medical Centre, CA USA .
    Lester, Jenny
    Cedars Sinai Medical Centre, CA USA .
    Orsulic, Sandra
    Cedars Sinai Medical Centre, CA USA .
    Narod, Steven A.
    University of Toronto, Canada .
    Herzog, Josef
    City Hope National Medical Centre, CA USA .
    Sand, Sharon r.
    City Hope National Medical Centre, CA USA .
    Tognazzo, Silvia
    Ist Oncology Veneto IOV IRCCS, Italy .
    Agata, Simona
    Ist Oncology Veneto IOV IRCCS, Italy .
    Vaszko, Tibor
    National Institute Oncol, Hungary .
    Weaver, Joellen
    Fox Chase Cancer Centre, PA USA .
    Stavropoulou, Alexandra V.
    National Centre Science Research Demokritos, Greece .
    Buys, Saundra S.
    University of Utah, UT USA .
    Romero, Atocha
    Hospital Clin San Carlos, Spain .
    de la Hoya, Miguel
    Hospital Clin San Carlos, Spain .
    Aittomaki, Kristiina
    University of Helsinki, Finland .
    Muranen, Taru A.
    University of Helsinki, Finland .
    Duran, Mercedes
    University of Valladolid IBGM UVA, Spain .
    Chung, Wendy K.
    Columbia University, NY USA.
    Lasa, Adriana
    Hospital Santa Creu and Sant Pau, Spain .
    Dorfling, Cecilia M.
    University of Pretoria, South Africa .
    Miron, Alexander
    Dana Farber Cancer Institute, MA USA .
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain Biomed Network Rare Disease CIBERER, Spain .
    Senter, Leigha
    Ohio State University, OH USA .
    Huo, Dezheng
    University of Chicago, IL USA .
    Chan, Salina B.
    University of Calif San Francisco, CA USA .
    Sokolenko, Anna P.
    NN Petrov Oncology Research Institute, Russia .
    Chiquette, Jocelyne
    University of Quebec, Canada .
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia .
    Friebel, Tara M.
    University of Penn, PA USA .
    Agnarsson, Bjarni A.
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Lu, Karen H.
    University of Texas MD Anderson Cancer Centre, TX USA .
    Lejbkowicz, Flavio
    Clalit National Israeli Cancer Control Centre, Israel Carmel Hospital, Israel .
    James, Paul A.
    Peter MacCallum Cancer Centre, Australia .
    Hall, Per
    Karolinska Institute, Sweden .
    Dunning, Alison M.
    University of Cambridge, England .
    Tessier, Daniel
    Centre Innovat Genome Quebec, Canada McGill University, Canada .
    Cunningham, Julie
    Mayo Clin, MN USA.
    Slager, Susan L.
    Mayo Clin, MN USA .
    Wang, Chen
    Mayo Clin, MN USA .
    Hart, Steven
    Mayo Clin, MN USA .
    Stevens, Kristen
    Mayo Clin, MN USA .
    Simard, Jacques
    Centre Hospital University of Quebec, Canada University of Laval, Canada .
    Pastinen, Tomi
    McGill University, Canada.
    Pankratz, Vernon S.
    Mayo Clin, MN USA .
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY USA .
    Easton, Douglas F.
    University of Cambridge, England .
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research, Australia .
    Antoniou, Antonis C.
    University of Cambridge, England.
    Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 3Article in journal (Refereed)
    Abstract [en]

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

  • 8.
    Cox, DavidG
    et al.
    University of Lyon 1.
    Simard, Jacques
    Centre Hospital University of Quebec.
    Sinnett, Daniel
    St Justine University of Health Centre.
    Hamdi, Yosr
    Centre Hospital University of Quebec.
    Soucy, Penny
    Centre Hospital University of Quebec.
    Ouimet, Manon
    St Justine University of Health Centre.
    Barjhoux, Laure
    University of Lyon 1.
    Verny-Pierre, Carole
    University of Lyon 1.
    McGuffog, Lesley
    University of Cambridge.
    Healey, Sue
    Queensland Institute Medical Research.
    Szabo, Csilla
    University of Delaware.
    H Greene, Mark
    US National Cancer Institute.
    Mai, Phuong L
    US National Cancer Institute.
    Andrulis, Irene L
    University of Toronto.
    Thomassen, Mads
    Odense University Hospital.
    Gerdes, Anne-Marie
    Copenhagen University Hospital.
    Caligo, Maria A
    University Hospital Pisa.
    Friedman, Eitan
    Chaim Sheba Medical Centre.
    Laitman, Yael
    Chaim Sheba Medical Centre.
    Kaufman, Bella
    Chaim Sheba Medical Centre.
    S Paluch, Shani
    Tel Aviv University.
    Borg, Ake
    University of Lund Hospital.
    Karlsson, Per
    Sahlgrens University Hospital.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Barbany Bustinza, Gisela
    Karolinska University Hospital.
    Nathanson, KatherineL
    University of Penn.
    Domchek, Susan M
    University of Penn.
    Rebbeck, Timothy R
    University of Penn.
    Benitez, Javier
    Spanish National Cancer Research Centre.
    Hamann, Ute
    Deutsch Krebsforschungszentrum.
    Rookus, Matti A
    Netherlands Cancer Institute.
    van den Ouweland, AnsM W
    Erasmus University.
    Ausems, Margreet G E M
    University of Medical Centre Utrecht.
    Aalfs, CoraM
    University of Amsterdam.
    van Asperen, Christi J
    Leiden University.
    Devilee, Peter
    Leiden University.
    Gille, Hans J J P
    Vrije University of Amsterdam Medical Centre.
    Peock, Susan
    University of Cambridge.
    Frost, Debra
    University of Cambridge.
    Evans, DGareth
    Central Manchester University Hospital NHS Fdn Trust.
    Eeles, Ros
    Institute Cancer Research, Surrey.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust.
    Adlard, Julian
    Yorkshire Regional Genet Serv.
    Paterson, Joan
    Addenbrookes Hospital.
    Eason, Jacqueline
    Nottingham University Hospital NHS Trust.
    Godwin, Andrew K
    Fox Chase Cancer Centre.
    Remon, Marie-Alice
    Institute Curie.
    Moncoutier, Virginie
    Institute Curie.
    Gauthier-Villars, Marion
    Institute Curie.
    Lasset, Christine
    University of Lyon 1.
    Giraud, Sophie
    Centre Leon Berard.
    Hardouin, Agnes
    Centre Francois Baclesse.
    Berthet, Pascaline
    Centre Francois Baclesse.
    Sobol, Hagay
    University of Aix Marseille 2.
    Eisinger, Francois
    Institute Paoli Calmettes.
    Bressac de Paillerets, Brigitte
    Institute Cancerol Gustave Roussy.
    Caron, Olivier
    Institute Cancerol Gustave Roussy.
    Delnatte, Capucine
    Centre Rene Gauducheau.
    Goldgar, David
    University of Utah.
    Miron, Alex
    Dana Farber Cancer Institute.
    Ozcelik, Hilmi
    Mt Sinai Hospital.
    Buys, Saundra
    University of Utah.
    Southey, Melissa C
    University of Melbourne.
    Terry, MaryBeth
    Columbia University.
    Singer, ChristianF
    Medical University of Vienna.
    Dressler, Anne-Catharina
    Medical University of Vienna.
    Tea, Muy-Kheng
    Medical University of Vienna.
    Hansen, ThomasV O
    Copenhagen University Hospital.
    Johannsson, Oskar
    University of Iceland.
    Piedmonte, Marion
    Roswell Pk Cancer Institute.
    C Rodriguez, Gustavo
    University of Chicago.
    Basil, Jack B
    Good Samaritan Hospital.
    Blank, Stephanie
    NYU.
    Toland, Amanda E
    Ohio State University.
    Montagna, Marco
    Institute Oncology Veneto IOV IRCCS.
    Isaacs, Claudine
    Georgetown University.
    Blanco, Ignacio
    Catalan Institute Oncol.
    Gayther, Simon A
    University of So Calif.
    Moysich, KirstenB
    Roswell Pk Cancer Institute.
    Schmutzler, Rita K
    University Hospital Cologne.
    Wappenschmidt, Barbara
    University Hospital Cologne.
    Engel, Christoph
    University of Leipzig.
    Meindl, Alfons
    Technical University of Munich.
    Ditsch, Nina
    University of Munich.
    Arnold, Norbert
    University of Kiel.
    Niederacher, Dieter
    University of Dusseldorf.
    Sutter, Christian
    University of Heidelberg.
    Gadzicki, Dorothea
    Hannover Medical Sch.
    Fiebig, Britta
    University of Regensburg.
    Caldes, Trinidad
    Hospital Clin San Carlos.
    Laframboise, Rachel
    University of Laval.
    Nevanlinna, Heli
    Helsinki University Central Hospital.
    Chen, Xiaoqing
    Queensland Institute Medical Research.
    Beesley, Jonathan
    Queensland Institute Medical Research.
    Spurdle, Amanda B
    Queensland Institute Medical Research.
    Neuhausen, Susan L
    Beckman Research Institute City Hope.
    Ding, Yuan C
    Beckman Research Institute City Hope.
    Couch, FergusJ
    Mayo Clin.
    Wang, Xianshu
    Mayo Clin.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT.
    Bernard, Loris
    Ist Europeo Oncology IEO.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Easton, Douglas F
    University of Cambridge.
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research.
    Antoniou, Antonis C
    University of Cambridge.
    Stoppa-Lyonnet, Dominique
    Institute Curie.
    Mazoyer, Sylvie
    University of Lyon 1.
    Sinilnikova, Olga M
    University of Lyon 1.
    Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers2011In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 23, p. 4732-4747Article in journal (Refereed)
    Abstract [en]

    Mutations in the BRCA1 gene substantially increase a womans lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

  • 9.
    Ding, Yuan C
    et al.
    City Hope National Medical Centre, CA, USA .
    McGuffog, Lesley
    University of Cambridge Worts Causeway, England .
    Healey, Sue
    Royal Brisbane Hospital, Australia .
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Paluch-Shimon, Shani
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Kaufman, Bella
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Liljegren, Annelie
    Karolinska University Hospital, Sweden .
    Lindblom, Annika
    Karolinska University Hospital, Sweden .
    Olsson, Hakan
    University of Lund Hospital, Sweden .
    Kristoffersson, Ulf
    University of Lund Hospital, Sweden .
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umeå University, Sweden .
    Domchek, Susan M
    University of Penn, PA, USA .
    Nathanson, Katherine L
    University of Penn, PA, USA .
    Rebbeck, Timothy R
    University of Penn, PA, USA .
    Jakubowska, Anna
    Pomeranian Medical University, Poland .
    Lubinski, Jan
    Pomeranian Medical University, Poland .
    Jaworska, Katarzyna
    Pomeranian Medical University, Poland .
    Durda, Katarzyna
    Pomeranian Medical University, Poland .
    Gronwald, Jacek
    Pomeranian Medical University, Poland .
    Huzarski, Tomasz
    Pomeranian Medical University, Poland .
    Cybulski, Cezary
    Pomeranian Medical University, Poland .
    Byrski, Tomasz
    Pomeranian Medical University, Poland .
    Osorio, Ana
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain .
    Ramony Cajal, Teresa
    Hospital Santa Creu and Sant Pau, Spain .
    Stavropoulou, Alexandra V
    National Centre Science Research Demokritos, Greece .
    Benitez, Javier
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain .
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Rookus, Matti
    Netherlands Cancer Institute, Netherlands .
    Aalfs, Cora M
    University of Amsterdam, Netherlands .
    de Lange, Judith L
    Netherlands Cancer Institute, Netherlands .
    Meijers-Heijboer, Hanne E J
    Vrije University of Amsterdam Medical Centre, Netherlands .
    Oosterwijk, Jan C
    University of Groningen, Netherlands .
    van Asperen, Christi J
    Leiden University, Netherlands .
    Gomez Garcia, Encarna B
    MUMC, Netherlands .
    Hoogerbrugge, Nicoline
    Radboud University of Nijmegen, Netherlands .
    Jager, Agnes
    Erasmus University, Netherlands .
    van der Luijt, Rob B
    University of Medical Centre Utrecht, Netherlands .
    Easton, Douglas F
    University of Cambridge, England .
    Peock, Susan
    University of Cambridge, England .
    Frost, Debra
    University of Cambridge, England .
    Ellis, Steve D
    University of Cambridge, England .
    Platte, Radka
    University of Cambridge, England .
    Fineberg, Elena
    University of Cambridge, England .
    Evans, D Gareth
    Central Manchester University Hospital NHS Fdn Trust, England .
    Lalloo, Fiona
    Central Manchester University Hospital NHS Fdn Trust, England .
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust, England .
    Eeles, Ros
    Institute Cancer Research, England Royal Marsden NHS Fdn Trust, England .
    Adlard, Julian
    Yorkshire Regional Genet Serv, England .
    Davidson, Rosemarie
    Yorkhill Hospital, Scotland .
    Eccles, Diana
    University Hospital Southampton NHS Fdn Trust, England .
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, England .
    Cook, Jackie
    Sheffield Childrens Hospital, England .
    Brewer, Carole
    Royal Devon and Exeter Hospital, England .
    Tischkowitz, Marc
    University of Cambridge, England .
    Godwin, Andrew K
    University of Kansas, KS, USA .
    Pathak, Harsh
    University of Kansas, KS, USA .
    Stoppa-Lyonnet, Dominique
    Institute Curie, France Institute Curie, France University of Paris 05, France .
    Sinilnikova, Olga M
    University of Lyon 1, France Centre Hospital University of Lyon, France .
    Mazoyer, Sylvie
    University of Lyon 1, France .
    Barjhoux, Laure
    University of Lyon 1, France .
    Leone, Melanie
    Centre Hospital University of Lyon, France .
    Gauthier-Villars, Marion
    Institute Curie, France .
    Caux-Moncoutier, Virginie
    Institute Curie, France .
    de Pauw, Antoine
    Institute Curie, France .
    Hardouin, Agnes
    Centre Francois Baclesse, France .
    Berthet, Pascaline
    Centre Francois Baclesse, France .
    Dreyfus, Helene
    CHU Grenoble, France University of Grenoble, France .
    Fert Ferrer, Sandra
    Hotel Dieu Centre Hospital, France .
    Collonge-Rame, Marie-Agnes
    CHU Besancon, France .
    Sokolowska, Johanna
    Nancy University, France .
    Buys, Saundra
    University of Utah, UT, USA .
    Daly, Mary
    Fox Chase Cancer Centre, PA, USA .
    Miron, Alex
    Dana Farber Cancer Institute, MA, USA .
    Terry, Mary Beth
    Columbia University, NY, USA .
    Chung, Wendy
    Columbia University, NY, USA .
    John, Esther M
    Cancer Prevent Institute Calif, CA, USA Stanford University, CA, USA Stanford Cancer Institute, CA, USA .
    Southey, Melissa
    University of Melbourne, Australia .
    Goldgar, David
    University of Utah, UT, USA .
    Singer, Christian F
    Medical University of Vienna, Austria .
    Tea, Muy-Kheng Maria
    Medical University of Vienna, Austria .
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna, Austria .
    Fink-Retter, Anneliese
    Medical University of Vienna, Austria .
    Hansen, Thomas V O
    Copenhagen University Hospital, Denmark .
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark .
    Johannsson, Oskar T
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Offit, Kenneth
    Clin Cancer Genet Lab, NY, USA .
    Sarrel, Kara
    Clin Cancer Genet Lab, NY, USA .
    Gaudet, Mia M
    Amer Cancer Soc, GA, USA .
    Vijai, Joseph
    Clin Cancer Genet Lab, NY, USA .
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY, USA .
    Piedmonte, Marion R
    Roswell Pk Cancer Institute, NY, USA .
    Andrews, Lesley
    Australia New Zealand Gynaecol Oncology Grp, Australia .
    Cohn, David
    Ohio State University, OH, USA .
    DeMars, Leslie R
    Dartmouth Hitchcock Medical Centre, NH, USA .
    DiSilvestro, Paul
    Brown University, RI, USA .
    Rodriguez, Gustavo
    NorthShore University of Health Syst, IL, USA .
    Ewart Toland, Amanda
    Ohio State University, OH, USA Ohio State University, OH, USA .
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS, Italy .
    Agata, Simona
    Ist Oncology Veneto IOV IRCCS, Italy .
    Imyanitov, Evgeny
    NN Petrov Oncology Research Institute, Russia .
    Isaacs, Claudine
    Georgetown University, DC, USA .
    Janavicius, Ramunas
    Vilnius University Hospital, Lithuania .
    Lazaro, Conxi
    Institute Catala Oncol, Spain .
    Blanco, Ignacio
    IDIBELL Catalan Institute Oncol, Spain .
    Ramus, Susan J
    University of So Calif, CA, USA .
    Sucheston, Lara
    Roswell Pk Cancer Institute, NY, USA .
    Karlan, Beth Y
    Cedars Sinai Medical Centre, CA, USA .
    Gross, Jenny
    Cedars Sinai Medical Centre, CA, USA .
    Ganz, Patricia A
    University of Calif Los Angeles, CA, USA .
    Beattie, Mary S
    University of Calif San Francisco, CA, USA .
    Schmutzler, Rita K
    University Hospital Cologne, Germany .
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany .
    Meindl, Alfons
    Technical University of Munich, Germany .
    Arnold, Norbert
    University of Kiel, Germany .
    Niederacher, Dieter
    University of Dusseldorf, Germany .
    Preisler-Adams, Sabine
    University of Munster, Germany .
    Gadzicki, Dorotehea
    Hannover Medical Sch, Germany .
    Varon-Mateeva, Raymonda
    Charite, Germany .
    Deissler, Helmut
    University Hospital Ulm, Germany .
    Gehrig, Andrea
    University of Wurzburg, Germany .
    Sutter, Christian
    University of Heidelberg Hospital, Germany .
    Kast, Karin
    Technical University of Dresden, Germany .
    Nevanlinna, Heli
    University of Helsinki, Finland .
    Aittomaki, Kristiina
    Centre Hospital University of Quebec, Canada University of Laval, Canada .
    Spurdle, Amanda B
    Royal Brisbane Hospital, Australia .
    Beesley, Jonathan
    Royal Brisbane Hospital, Australia .
    Chen, Xiaoqing
    Royal Brisbane Hospital, Australia .
    Tomlinson, Gail E
    University of Texas Health Science Centre San Antonio, TX, USA.
    Weitzel, Jeffrey
    City Hope National Medical Centre, CA, USA .
    Garber, Judy E
    Harvard University, MA, USA .
    Olopade, Olufunmilayo I
    University of Chicago, IL, USA .
    Rubinstein, Wendy S
    NorthShore University of HealthSyst, IL, USA .
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA, USA .
    Blum, Joanne L
    Baylor Charles A Sammons Cancer Centre, TX, USA .
    Narod, Steven A
    Womens Coll Hospital, Canada .
    Brummel, Sean
    Harvard University, MA, USA .
    Gillen, Daniel L
    University of Calif Irvine, CA USA .
    Lindor, Noralane
    Mayo Clin, MN, USA .
    Fredericksen, Zachary
    Mayo Clin, MN, USA .
    Pankratz, Vernon S
    Mayo Clin, MN, USA .
    Couch, Fergus J
    Mayo Clin, MN, USA .
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Greene, Mark H
    NCI, MD, USA .
    Loud, Jennifer T
    NCI, MD, USA .
    Mai, Phuong L
    NCI, MD, USA .
    Andrulis, Irene L
    University of Toronto, Canada .
    Glendon, Gord
    University of Toronto, Canada .
    Gerdes, Anne-Marie
    Odense University Hospital, Denmark .
    Birk Jensen, Uffe
    Skejby Hospital, Denmark .
    Skytte, Anne-Bine
    Vejle Hospital, Denmark .
    Caligo, Maria A
    University of Pisa, Italy University Hospital Pisa, Italy .
    Lee, Andrew
    University of Cambridge Worts Causeway, England .
    Chenevix-Trench, Georgia
    Royal Brisbane Hospital, Australia .
    Antoniou, Antonis C
    University of Cambridge Worts Causeway, England .
    Neuhausen, Susan L
    City Hope National Medical Centre, CA, USA .
    A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 8, p. 1362-1370Article in journal (Refereed)
    Abstract [en]

    Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. less thanbrgreater than less thanbrgreater thanMethods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. less thanbrgreater than less thanbrgreater thanResults: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). less thanbrgreater than less thanbrgreater thanConclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. less thanbrgreater than less thanbrgreater thanImpact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

  • 10.
    Hayat Roshanai, Afsaneh
    et al.
    BMC, Sweden Uppsala University, Sweden .
    Lampic, Claudia
    Karolinska Institute, Sweden Uppsala University, Sweden .
    Ingvoldstad, Charlotta
    Uppsala University, Sweden .
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Bjorvatn, Chathrine
    University of Bergen, Norway .
    Rosenquist, Richard
    Uppsala University, Sweden .
    Nordin, Karin
    University of Bergen, Norway Uppsala University, Sweden .
    What Information Do Cancer Genetic Counselees Prioritize?2012In: Journal of Genetic Counseling, ISSN 1059-7700, E-ISSN 1573-3599, Vol. 21, no 4, p. 510-526Article in journal (Refereed)
    Abstract [en]

    This study explored the informational needs of individuals attending genetic counseling for hereditary cancer, using a free-choice and a forced choice method. Prior to the consultation the informational needs of 334 counselees from Sweden and Norway were assessed by the QUOTE-gene (ca) questionnaire and by a study specific forced choice method, using Q-methodology. Questionnaire responses indicated that counselees major concerns pertained to the need to be taken seriously, to be provided with sufficient risk estimation and medical/genetic information and to be involved in the decision making process. Furthermore, prior to counseling, counselees noted that the counselors consideration and skillfulness were also extremely important. Analysis of the Q-sorting results revealed that counselees needs could be assigned to one of five groups: the "need for facts; caring communication and medical information; information and support in communicating the genetic information to others; practical care and practical/medical information". Particularly noteworthy, counselees with varying backgrounds characteristics prioritized different needs. Cancer genetic counselees probably have different needs due to their medical and demographic background when attending genetic counseling. Addressing counselees specific concerns more sufficiently and thereby increasing the overall effectiveness of the counseling session requires increased insight into individual needs, by for instance, utilizing screening methods such as QUOTE-gene (ca) prior to the counseling session.

  • 11.
    Jakubowska, A
    et al.
    Pomeranian Medical University, Poland .
    Rozkrut, D
    University of Szczecin, Poland .
    Antoniou, A
    University of Cambridge, England .
    Hamann, U
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Scott, R J
    University of Newcastle, Australia Hunter Medical Research Institute, Australia .
    McGuffog, L
    University of Cambridge, England .
    Healy, S
    Queensland Institute Medical Research, Australia .
    Sinilnikova, O M
    Centre Hospital University of Lyon, France University of Lyon 1, France .
    Rennert, G
    Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel .
    Lejbkowicz, F
    Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel .
    Flugelman, A
    Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel .
    Andrulis, I L
    Cancer Care Ontario, Canada Mt Sinai Hospital, Canada .
    Glendon, G
    Cancer Care Ontario, Canada Mt Sinai Hospital, Canada .
    Ozcelik, H
    Mt Sinai Hospital, Canada .
    Thomassen, M
    Odense University Hospital, Denmark .
    Paligo, M
    University Hospital Pisa, Italy .
    Aretini, P
    University Hospital Pisa, Italy .
    Kantala, J
    Karolinska University Hospital, Sweden .
    Aroer, B
    Karolinska University Hospital, Sweden .
    Von Wachenfeldt, A
    Karolinska University Hospital, Sweden .
    Liljegren, A
    Karolinska University Hospital, Sweden .
    Loman, N
    University of Lund Hospital, Sweden .
    Herbst, K
    University of Lund Hospital, Sweden .
    Kristoffersson, U
    University of Lund Hospital, Sweden .
    Rosenquist, R
    Uppsala University, Sweden .
    Karlsson, P
    Sahlgrens University Hospital, Sweden .
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, B
    Umeå University, Sweden .
    Nathanson, K L
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    Domchek, S M
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    Byrski, T
    Pomeranian Medical University, Poland .
    Huzarski, T
    Pomeranian Medical University, Poland .
    Gronwald, J
    Pomeranian Medical University, Poland .
    Menkiszak, J
    Pomeranian Medical University, Poland .
    Cybulski, C
    Pomeranian Medical University, Poland .
    Serrano, P
    Pomeranian Medical University, Poland .
    Osorio, A
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain .
    Cajal, T R
    Hospital Santa Creu and Sant Pau, Spain .
    Tsitlaidou, M
    National Centre Science Research Demokritos, Greece .
    Benitez, J
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain .
    Gilbert, M
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Rookus, M
    Netherlands Cancer Institute, Netherlands .
    Aalfs, C M
    University of Amsterdam, Netherlands .
    Kluijt, I
    Netherlands Cancer Institute, Netherlands .
    Boessenkool-Pape, J L
    Netherlands Cancer Institute, Netherlands .
    Meijers-Heijboer, H E J
    Vrije University of Amsterdam Medical Centre, Netherlands .
    C Oosterwijk, J
    University of Groningen, Netherlands .
    J van Asperen, C
    Leiden University of Medical Centre, Netherlands .
    J Blok, M
    University Hospital Maastricht, Netherlands .
    R Nelen, M
    Radboud University of Nijmegen Medical Centre, Netherlands .
    M W van den Ouweland, A
    Erasmus MC, Netherlands .
    Seynaeve, C
    Erasmus MC, Netherlands .
    B van der Luijt, R
    University of Medical Centre Utrecht, Netherlands .
    Devilee, P
    Leiden University of Medical Centre, Netherlands Leiden University of Medical Centre, Netherlands .
    F Easton, D
    University of Cambridge, England .
    Peock, S
    University of Cambridge, England .
    Frost, D
    University of Cambridge, England .
    Platte, R
    University of Cambridge, England .
    D Ellis, S
    University of Cambridge, England .
    Fineberg, E
    University of Cambridge, England .
    G Evans, D
    NHS Fdn Trust, England .
    Lalloo, F
    NHS Fdn Trust, England .
    Eeles, R
    Royal Marsden NHS Fdn Trust, England .
    Jacobs, C
    Guys and St Thomas NHS Fdn Trust, England .
    Adlard, J
    Yorkshire Regional Genet Serv, England .
    Davidson, R
    Yorkhill Hospital, Scotland .
    Eccles, D
    University of Southampton, England .
    Cole, T
    Birmingham Womens Hospital Healthcare NHS Trust, England .
    Cook, J
    Sheffield Childrens Hospital, England .
    Godwin, A
    University of Kansas Medical Centre, KS USA .
    Bove, B
    Fox Chase Cancer Centre, PA 19111 USA .
    Stoppa-Lyonnet, D
    Institute Curie, France Institute Curie, France University of Paris 05, France .
    Caux-Moncoutier, V
    Institute Curie, France .
    Belotti, M
    Institute Curie, France .
    Tirapo, C
    Institute Curie, France .
    Mazoyer, S
    University of Lyon 1, France .
    Barjhoux, L
    University of Lyon 1, France .
    Boutry-Kryza, N
    Centre Hospital University of Lyon, France .
    Pujol, P
    CHU Arnaud de Villeneuve, France CRCM dAurelle, France .
    Coupier, I
    CHU Arnaud de Villeneuve, France CRLCC Val dAurelle, France .
    Peyrat, J-P
    Centre Oscar Lambret, France .
    Vennin, P
    Centre Oscar Lambret, France .
    Muller, D
    CLCC Paul Strauss, France .
    Fricker, J-P
    CLCC Paul Strauss, France .
    Venat-Bouvet, L
    Centre Hospital University of Dupuytren, France .
    Johannsson, OTh
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Isaacs, C
    Georgetown University, DC USA .
    Schmutzler, R
    University Hospital Cologne, Germany University Hospital Cologne, Germany .
    Wappenschmidt, B
    University Hospital Cologne, Germany University Hospital Cologne, Germany .
    Meindl, A
    University of Munich, Germany .
    Arnold, N
    University of Kiel, Germany .
    Varon-Mateeva, R
    Institute Human Genet, Germany .
    Niederacher, D
    University of Dusseldorf, Germany .
    Sutter, C
    University of Heidelberg Hospital, Germany .
    Deissler, H
    University Hospital Ulm, Germany .
    Preisler-Adams, S
    University of Munster, Germany .
    Simard, J
    University of Laval, Canada Centre Hospital University of Quebec, Canada .
    Soucy, P
    University of Laval, Canada Centre Hospital University of Quebec, Canada .
    Durocher, F
    University of Laval, Canada Centre Hospital University of Quebec, Canada .
    Chenevix-Trench, G
    Queensland Institute Medical Research, Australia .
    Beesley, J
    Queensland Institute Medical Research, Australia .
    Chen, X
    Queensland Institute Medical Research, Australia .
    Rebbeck, T
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    Couch, F
    Mayo Clin, MN USA Mayo Clin, MN USA .
    Wang, X
    Mayo Clin, MN USA .
    Lindor, N
    Mayo Clin, MN USA .
    Fredericksen, Z
    Mayo Clin, MN USA .
    S Pankratz, V
    Mayo Clin, MN USA .
    Peterlongo, P
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Bonanni, B
    Ist Europeo Oncol, Italy .
    Fortuzzi, S
    Fdn Ist FIRC Oncology Mol, Italy 84 Cogentech Cancer Genet Test Lab, Italy .
    Peissel, B
    Fdn IRCCS Ist Nazl Tumori INT, Italy .
    Szabo, C
    Mayo Clin, MN USA .
    L Mai, P
    Department Health and Human Serv, MD 20852 USA .
    T Loud, J
    Department Health and Human Serv, MD 20852 USA .
    Lubinski, J
    Pomeranian Medical University, Poland .
    Association of PHB 1630 C andgt; T and MTHFR 677 C andgt; T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, no 12, p. 2016-2024Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. less thanbrgreater than less thanbrgreater thanMETHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 Candgt;T (rs6917) polymorphism and the MTHFR 677 Candgt;T (rs1801133) polymorphism, respectively. less thanbrgreater than less thanbrgreater thanRESULTS: There was no evidence of association between the PHB 1630 Candgt;T and MTHFR 677 Candgt;T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 Candgt;T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. less thanbrgreater than less thanbrgreater thanCONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

  • 12.
    Jansson, Agneta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Carlsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Olsson, Anette
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Storm, Petter
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Margolin, Sara
    Department of Oncology, Karolinska University Hospital/ Södersjukhuset, Stockholm, Sweden.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Medical Genetics. Linköping University, Faculty of Health Sciences.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindblom, Annika
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer2007In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 106, no 1, p. 57-64Article in journal (Refereed)
    Abstract [en]

    In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17β-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.

  • 13.
    Johansson, Joel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Sahin, Christofer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Pestoff, Rebecka
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Edsjö, Anders
    Sahlgrenska University Hospital Göteborg .
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    A Novel SMAD4 Mutation Causing Severe Juvenile Polyposis Syndrome with Protein Losing Enteropathy, Immunodeficiency, and Hereditary Haemorrhagic Telangiectasia.2015In: Case Reports in Gastrointestinal Medicine, ISSN 2090-6528, E-ISSN 2090-6536, Vol. 2015, p. 1-5, article id 140616Article in journal (Refereed)
    Abstract [en]

    Juvenile polyposis syndrome (JPS) is a rare genetic disorder characterized by juvenile polyps of the gastrointestinal tract. We present a new pathogenic mutation of the SMAD4 gene and illustrate the need for a multidisciplinary health care approach to facilitate the correct diagnosis. The patient, a 47-year-old Caucasian woman, was diagnosed with anaemia at the age of 12. During the following 30 years, she developed numerous gastrointestinal polyps. The patient underwent several operations, and suffered chronic abdominal pain, malnutrition, and multiple infections. Screening of the SMAD4 gene revealed a novel, disease-causing mutation. In 2012, the patient suffered hypoalbuminemia and a large polyp in the small bowel was found. Gamma globulin was given but the patient responded with fever and influenza-like symptoms and refused more treatment. The patient underwent surgery in 2014 and made an uneventful recovery. At follow-up two months later albumin was 38 g/L and IgG was 6.9 g/L. Accurate diagnosis is essential for medical care. For patients with complex symptomatology, often with rare diseases, this is best provided by multidisciplinary teams including representatives from clinical genetics. Patients with a SMAD4 mutation should be followed up both for JPS and haemorrhagic hereditary telangiectasia and may develop protein loosing enteropathy and immunodeficiency.

  • 14.
    Karimi, Masoud
    et al.
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    von Salomé, Jenny
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Aravidis, Christos
    Department of Clinical Genetics, Akademiska University Hospital, Uppsala, Sweden.
    Silander, Gustav
    Department of Clinical Genetics, Norrlands University Hospital, Umeå, Sweden.
    Stenmark Askmalm, Marie
    Region Östergötland, Center for Diagnostics, Clinical genetics. Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Henriksson, Isabelle
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; 8Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Gebre-Medhin, Samuel
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; 8Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Frödin, Jan-Erik
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Björck, Erik
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Lagerstedt-Robinson, Kristina
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Lindblom, Annika
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Tham, Emma
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families2018In: Hereditary Cancer in Clinical Practice, ISSN 1731-2302, E-ISSN 1897-4287, Vol. 16, article id 16Article in journal (Refereed)
    Abstract [en]

    Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families.

  • 15.
    Kirchhoff, Tomas
    et al.
    Mem Sloan Kettering Cancer Centre, USA.
    Gaudet, Mia M.
    Mem Sloan Kettering Cancer Centre, USA.
    Antoniou, Antonis C.
    University of Cambridge, England.
    McGuffog, Lesley
    University of Cambridge, England.
    Humphreys, Manjeet K.
    University of Cambridge, England.
    Dunning, Alison M.
    University of Cambridge, England.
    Bojesen, Stig E.
    University of Copenhagen, Denmark.
    Nordestgaard, Borge G.
    University of Copenhagen, Denmark University of Copenhagen, Denmark .
    Flyger, Henrik
    University of Copenhagen, Denmark .
    Kang, Daehee
    Seoul National University, South Korea National Cancer Centre, South Korea University of Ulsan, South Korea .
    Yoo, Keun-Young
    Seoul National University, South Korea National Cancer Centre, South Korea University of Ulsan, South Korea .
    Noh, Dong-Young
    Seoul National University, South Korea National Cancer Centre, South Korea University of Ulsan, South Korea .
    Ahn, Sei-Hyun
    Seoul National University, South Korea National Cancer Centre, South Korea University of Ulsan, South Korea .
    Dork, Thilo
    Hannover Medical Sch, Germany Hannover Medical Sch, Germany .
    Schuermann, Peter
    Hannover Medical Sch, Germany Hannover Medical Sch, Germany .
    H. Karstens, Johann
    Hannover Medical Sch, Germany Hannover Medical Sch, Germany .
    Hillemanns, Peter
    Hannover Medical Sch, Germany Hannover Medical Sch, Germany .
    J. Couch, Fergus
    Mayo Clin, MN USA Mayo Clin, MN USA .
    Olson, Janet
    Mayo Clin, MN USA .
    Vachon, Celine
    Mayo Clin, MN USA .
    Wang, Xianshu
    Mayo Clin, MN USA .
    Cox, Angela
    University of Sheffield, England .
    Brock, Ian
    University of Sheffield, England .
    Elliott, Graeme
    University of Sheffield, England .
    W. R. Reed, Malcolm
    University of Sheffield, England .
    Burwinkel, Barbara
    German Cancer Research Centre, Germany .
    Meindl, Alfons
    Technical University of Munich, Germany .
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany University of Tubingen, Germany University of Tubingen, Germany .
    Hamann, Ute
    Deutsch Krebsforschungszentrum, Germany .
    Ko, Yon-Dschun
    Evangel Kliniken Bonn gGmbH, Germany .
    Broeks, Annegien
    Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands .
    K. Schmidt, Marjanka
    Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands .
    J. Van t Veer, Laura
    Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands .
    M. Braaf, Linde
    Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands .
    Johnson, Nichola
    Institute Cancer Research, England .
    Fletcher, Olivia
    Institute Cancer Research, England .
    Gibson, Lorna
    London School Hyg and Trop Med, England .
    Peto, Julian
    London School Hyg and Trop Med, England .
    Turnbull, Clare
    Institute Cancer Research, England .
    Seal, Sheila
    Institute Cancer Research, England .
    Renwick, Anthony
    Institute Cancer Research, England .
    Rahman, Nazneen
    Institute Cancer Research, England .
    Wu, Pei-Ei
    Academic Sinica, Taiwan .
    Yu, Jyh-Cherng
    Tri Serv Gen Hospital, Taiwan .
    Hsiung, Chia-Ni
    Academic Sinica, Taiwan .
    Shen, Chen-Yang
    Academic Sinica, Taiwan .
    C. Southey, Melissa
    University of Melbourne, Australia Cancer Council, Australia University of Melbourne, Australia .
    L. Hopper, John
    University of Melbourne, Australia .
    Hammet, Fleur
    University of Melbourne, Australia .
    Van Dorpe, Thijs
    Katholieke University of Leuven, Belgium .
    Dieudonne, Anne-Sophie
    Katholieke University of Leuven, Belgium .
    Hatse, Sigrid
    Katholieke University of Leuven, Belgium .
    Lambrechts, Diether
    Vesalius Research Centre, Belgium .
    L. Andrulis, Irene
    Cancer Care Ontario, Canada Mt Sinai Hospital, Canada University of Toronto, Canada .
    Bogdanova, Natalia
    NN Alexandrov Research Institute Oncology and Medical Radiol, Byelarus .
    Antonenkova, Natalia
    NN Alexandrov Research Institute Oncology and Medical Radiol, Byelarus .
    I. Rogov, Juri
    NN Alexandrov Research Institute Oncology and Medical Radiol, Byelarus .
    Prokofieva, Daria
    Russian Academic Science, Russia .
    Bermisheva, Marina
    Russian Academic Science, Russia .
    Khusnutdinova, Elza
    Russian Academic Science, Russia .
    J. van Asperen, Christi
    Leiden University, Netherlands .
    A. E. M. Tollenaar, Robert
    Leiden University, Netherlands .
    J. Hooning, Maartje
    Erasmus MC, Netherlands .
    Devilee, Peter
    Leiden University, Netherlands .
    Margolin, Sara
    Karolinska Institute, Sweden Karolinska University, Sweden .
    Lindblom, Annika
    Karolinska Institute, Sweden .
    L. Milne, Roger
    Spanish National Cancer Centre, Spain .
    Ignacio Arias, Jose
    Monte Naranco Hospital, Spain .
    Pilar Zamora, M.
    La Paz University Hospital, Spain .
    Benitez, Javier
    Spanish National Cancer Centre, Spain Centre Invest Biomed Red Enfermedades Rares, Spain .
    Severi, Gianluca
    Cancer Council, Australia University of Melbourne, Australia .
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    Cancer Council, Australia University of Melbourne, Australia .
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    Cancer Council, Australia University of Melbourne, Australia .
    B. Spurdle, Amanda
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Beesley, Jonathan
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Chen, Xiaoqing
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Holland, Helene
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Healey, Sue
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Wang-Gohrke, Shan
    University of Ulm, Germany .
    Chang-Claude, Jenny
    German Cancer Research Centre DFKZ, Germany .
    Mannermaa, Arto
    University of Eastern Finland, Finland Kuopio University Hospital, Finland .
    Kosma, Veli-Matti
    University of Eastern Finland, Finland Kuopio University Hospital, Finland .
    Kauppinen, Jaana
    University of Eastern Finland, Finland Kuopio University Hospital, Finland .
    Kataja, Vesa
    Vaasa Central Hospital, Finland Kuopio University Hospital, Finland .
    A. Agnarsson, Bjarni
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
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    University of Pisa, Italy Pisa University Hospital, Italy .
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    Fox Chase Cancer Centre, PA 19111 USA .
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    University of Helsinki, Finland .
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    University of Helsinki, Finland .
    Fredericksen, Zachary
    Mayo Clin, MN USA .
    Lindor, Noralane
    Mayo Clin, MN USA .
    L. Nathanson, Katherine
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    M. Domchek, Susan
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    Loman, Niklas
    University of Lund Hospital, Sweden .
    Karlsson, Per
    Sahlgrens University Hospital, Sweden .
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umeå University, Sweden .
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    Karolinska University Hospital, Sweden .
    B. L. Hogervorst, Frans
    Netherlands Cancer Institute, Netherlands .
    Verheus, Martijn
    Netherlands Cancer Institute, Netherlands .
    A. Rookus, Matti
    Netherlands Cancer Institute, Netherlands .
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    Erasmus MC, Netherlands .
    A. Oldenburg, Rogier
    Erasmus MC, Netherlands .
    J. Ligtenberg, Marjolijn
    Radboud University of Nijmegen, Netherlands .
    G. E. M. Ausems, Margreet
    University of Medical Centre Utrecht, Netherlands .
    M. Aalfs, Cora
    Amsterdam Medical Centre, Netherlands .
    J. P. Gille, Hans
    Vrije University, Netherlands .
    T. Wijnen, Juul
    Vrije University, Netherlands .
    B. Gomez Garcia, Encarna
    University Hospital Maastricht, Netherlands .
    Peock, Susan
    University of Cambridge, England .
    Cook, Margaret
    University of Cambridge, England .
    T. Oliver, Clare
    University of Cambridge, England .
    Frost, Debra
    University of Cambridge, England .
    Luccarini, Craig
    University of Cambridge, England .
    Pichert, Gabriella
    Guys and St Thomas NHS Fdn Trust, England .
    Davidson, Rosemarie
    Yorkhill Hospital, Scotland .
    Chu, Carol
    Yorkshire Regional Genet Serv, England .
    Eccles, Diana
    Princess Anne Hospital, England .
    Ong, Kai-Ren
    Birmingham Womens Hospital Healthcare NHS Trust, England .
    Cook, Jackie
    Sheffield Childrens Hospital, England .
    Douglas, Fiona
    Newcastle Tyne Hospital NHS Trust, England .
    Hodgson, Shirley
    University of London, England .
    Gareth Evans, D.
    Central Manchester University Hospital National Health Serv NHS Fdn, England .
    Eeles, Rosalind
    Institute Cancer Research, England Royal Marsden NHS Fdn Trust, England .
    Gold, Bert
    NCI, MD USA .
    D. P. Pharoah, Paul
    University of Cambridge, England University of Cambridge, England .
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10021 USA .
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    F. Easton, Douglas
    University of Cambridge, England University of Cambridge, England .
    Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/22012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6Article in journal (Refereed)
    Abstract [en]

    Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I-2 = 49.3%; p = less than0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95% CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

  • 16.
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    University of So Calif, CA USA.
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    Technical University of Munich, Germany.
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    Heidelberg University, Germany.
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    Latvian Biomed Research and Study Centre, Latvia.
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    Beth Israel Deaconess Medical Centre, MA 02215 USA.
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    DKFZ, Germany.
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    Georgetown University, DC USA.
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    McGill University, Canada.
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    NN Petrov Institute Oncol, Russia.
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    Pomeranian Medical University, Poland.
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    Pomeranian Medical University, Poland.
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    University of Pittsburgh, PA USA; Magee Womens Research Institute, PA USA; University of Pittsburgh, PA USA.
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    University of Pittsburgh, PA USA.
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    Dr Horst Schmidt Klin Wiesbaden, Germany; Klin Essen Mitte, Germany.
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    University of Malaya, Malaysia.
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    University of Malaya, Malaysia; University of Malaya, Malaysia.
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    Texas So University, TX 77004 USA.
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    Duke University, NC 27710 USA.
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    Rutgers Cancer Institute New Jersey, NJ USA.
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    Radboud University of Nijmegen, Netherlands.
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    Medical University of S Carolina, SC 29425 USA.
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    University of New Mexico, NM 87131 USA.
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    British Columbia Cancer Agency, Canada.
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    Pomeranian Medical University, Poland.
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    NCI, MD 20892 USA.
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    NCI, MD 20892 USA.
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    University of Copenhagen, Denmark.
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    University of Copenhagen, Denmark.
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    University of Copenhagen, Denmark.
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    University of Cambridge, England.
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    University of Cambridge, England.
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    Princess Anne Hospital, England.
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    University of Porto, Portugal; University of Glasgow, Scotland.
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    University of Copenhagen, Denmark.
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    University of Copenhagen, Denmark.
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    Glasgow Royal Infirm, Scotland.
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    Beatson West Scotland, Scotland.
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    Stanford University, CA 94305 USA.
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    Stanford University, CA 94305 USA.
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    Stanford University, CA 94305 USA.
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    NCI, MD 20892 USA.
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    Vanderbilt University, TN 37212 USA.
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    Vanderbilt University, TN 37212 USA.
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    Shanghai Cancer Institute, Peoples R China.
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    University of Toronto, Canada; Princess Margaret Hospital, Canada.
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    Yale School Public Heatlh, CT USA.
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    Mt Sinai Hospital, Canada.
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    University of Toronto, Canada.
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    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
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    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
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    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
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    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
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    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
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    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
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    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
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    University of Calif Irvine, CA USA.
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    University of Calif Irvine, CA USA.
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    UCL, England.
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    UCL, England.
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    University of Cambridge, England.
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    University of Cambridge, England; University of So Calif, CA USA.
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    University of So Calif, CA USA.
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    University of So Calif, CA USA.
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    University of So Calif, CA USA; University of So Calif, CA USA.
    Pike, Malcolm C.
    University of So Calif, CA USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Dansonka-Mieszkowska, Agnieszka
    Maria Sklodowska Curie Mem Cancer Centre, Poland.
    Timorek, Agnieszka
    Medical University of Warsaw, Poland; Brodnowski Hospital, Poland.
    Rzepecka, Iwona K.
    Maria Sklodowska Curie Mem Cancer Centre, Poland.
    Kupryjanczyk, Jolanta
    Maria Sklodowska Curie Mem Cancer Centre, Poland.
    Freedman, Matt
    Centre Funct Cancer Epigenet, MA USA.
    Noushmehr, Houtan
    University of Sao Paulo, Brazil.
    Easton, Douglas F.
    University of Cambridge, England.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Couch, Fergus J.
    Mayo Clin, MN USA; Mayo Clin, MN USA.
    Gayther, Simon
    University of So Calif, CA USA.
    Pharoah, Paul P.
    University of Cambridge, England.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Identification of six new susceptibility loci for invasive epithelial ovarian cancer2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 2, p. 164-171Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P less than 5 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

  • 17.
    Lagerstedt-Robinson, Kristina
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Rohlin, Anna
    Sahlgrens University Hospital, Sweden; University of Gothenburg, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Melin, Beatrice
    Umeå University, Sweden.
    Nordling, Margareta
    Sahlgrens University Hospital, Sweden; University of Gothenburg, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. University of Lund Hospital, Sweden.
    Lindblom, Annika
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Nilbert, M. E. F.
    Lund University, Sweden; University of Copenhagen, Denmark.
    Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population2016In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 36, no 5, p. 2823-2835Article in journal (Refereed)
    Abstract [en]

    Lynch syndrome caused by constitutional mismatch-repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.

  • 18.
    Lawrenson, Kate
    et al.
    University of Southern Calif, CA 90033 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Kar, Siddhartha
    University of Cambridge, England.
    McCue, Karen
    QIMR Berghofer Medical Research Institute, Australia.
    Kuchenbaeker, Karoline
    University of Cambridge, England.
    Michailidou, Kyriaki
    University of Cambridge, England.
    Tyrer, Jonathan
    University of Cambridge, England.
    Beesley, Jonathan
    QIMR Berghofer Medical Research Institute, Australia.
    Ramus, Susan J.
    University of Southern Calif, CA 90033 USA.
    Li, Qiyuan
    Xiamen University, Peoples R China; Dana Farber Cancer Institute, MA 02215 USA.
    Delgado, Melissa K.
    University of Southern Calif, CA 90033 USA.
    Lee, Janet M.
    University of Southern Calif, CA 90033 USA.
    Aittomaki, Kristiina
    University of Helsinki, Finland.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Anton-Culver, Hoda
    University of Calif Irvine, CA 92697 USA.
    Arndt, Volker
    German Cancer Research Centre, Germany.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Bandera, Elisa V.
    Rutgers Cancer Institute New Jersey, NJ 08903 USA.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Barkardottir, Rosa B.
    University of Iceland, Iceland; University of Iceland, Iceland.
    Barrowdale, Daniel
    University of Cambridge, England.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Benitez, Javier
    Spanish National Cancer Research Centre, Spain; Centre Invest Red Enfermedades Raras, Spain.
    Berchuck, Andrew
    Duke University, NC 27710 USA.
    Bisogna, Maria
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Bjorge, Line
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Blomqvist, Carl
    University of Helsinki, Finland.
    Blot, William
    Vanderbilt University, TN 37203 USA; Int Epidemiol Institute, MD 20850 USA.
    Bogdanova, Natalia
    Hannover Medical Sch, Germany.
    Bojesen, Anders
    Vejle Hospital, Denmark; Seoul National University, South Korea; Lunenfeld Tanenbaum Research Institute Mt Sinai Hospital, Canada.
    Bojesen, Stig E.
    University of Copenhagen, Denmark; Copenhagen University Hospital, Denmark; Copenhagen University Hospital, Denmark.
    Bolla, Manjeet K.
    University of Cambridge, England.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Borresen-Dale, Anne-Lise
    Oslo University Hospital, Norway; University of Oslo, Norway.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University of Tubingen, Germany; German Cancer Research Centre, Germany.
    Brennan, Paul
    Int Agency Research Canc, France.
    Brenner, Hermann
    German Cancer Research Centre, Germany; German Cancer Research Centre, Germany; German Cancer Research Centre, Germany.
    Bruinsma, Fiona
    Cancer Council Victoria, Australia.
    Brunet, Joan
    Catalan Institute Oncol, Spain.
    Ahmad Buhari, Shaik
    National University of Health Syst, Singapore.
    Burwinkel, Barbara
    German Cancer Research Centre, Germany; Heidelberg University, Germany.
    Butzow, Ralf
    University of Helsinki, Finland.
    Buys, Saundra S.
    University of Utah, UT 84112 USA.
    Cai, Qiuyin
    Vanderbilt University, TN 37203 USA.
    Caldes, Trinidad
    IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain.
    Campbell, Ian
    Peter MacCallum Cancer Centre, Australia.
    Canniotto, Rikki
    Roswell Pk Cancer Institute, NY 14263 USA.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany; University of Medical Centre Hamburg Eppendorf, Germany.
    Chiquette, Jocelyne
    University of Quebec, Canada.
    Choi, Ji-Yeob
    Seoul National University, South Korea.
    Claes, Kathleen B. M.
    University of Ghent, Belgium.
    Cook, Linda S.
    University of New Mexico, NM 87131 USA.
    Cox, Angela
    University of Sheffield, England.
    Cramer, Daniel W.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Cross, Simon S.
    University of Sheffield, England.
    Cybulski, Cezary
    Pomeranian Medical University, Poland.
    Czene, Kamila
    Karolinska Institute, Sweden.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Damiola, Francesca
    University of Lyon, France.
    Dansonka-Mieszkowska, Agnieszka
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Darabi, Hatef
    Karolinska Institute, Sweden.
    Dennis, Joe
    University of Cambridge, England.
    Devilee, Peter
    Leiden University, Netherlands.
    Diez, Orland
    University Hospital Vall Hebron, Spain; University of Autonoma Barcelona, Spain.
    Doherty, Jennifer A.
    Geisel School Medical Dartmouth, NH 03755 USA.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    Doerk, Thilo
    Hannover Medical Sch, Germany.
    Dumont, Martine
    University of Laval, Canada.
    Ehrencrona, Hans
    Uppsala University, Sweden; University of Lund Hospital, Sweden.
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark.
    Ellis, Steve
    University of Cambridge, England.
    Engel, Christoph
    University of Leipzig, Germany.
    Lee, Eunjung
    University of Southern Calif, CA 90033 USA.
    Gareth Evans, D.
    University of Manchester, England.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany; University of Calif Los Angeles, CA 90095 USA.
    Feliubadalo, Lidia
    Catalan Institute Oncol, Spain.
    Figueroa, Jonine
    NCI, MD 20892 USA.
    Flesch-Janys, Dieter
    University of Medical Centre Hamburg Eppendorf, Germany; University of Medical Centre Hamburg Eppendorf, Germany.
    Fletcher, Olivia
    Institute Cancer Research, England.
    Flyger, Henrik
    Copenhagen University Hospital, Denmark.
    Foretova, Lenka
    Masaryk Mem Cancer Institute, Czech Republic; Medical Fac MU, Czech Republic.
    Fostira, Florentia
    Aghia Paraskevi Attikis, Greece.
    Foulkes, William D.
    McGill University, Canada.
    Fridley, Brooke L.
    University of Kansas, KS 66103 USA.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Frost, Debra
    University of Cambridge, England.
    Gambino, Gaetana
    University of and University Hospital Pisa, Italy.
    Ganz, Patricia A.
    Jonsson Comprehens Cancer Centre, CA 90024 USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA 02215 USA.
    Garcia-Closas, Montserrat
    NCI, MD 20892 USA; Institute Cancer Research, England.
    Gentry-Maharaj, Aleksandra
    UCL EGA Institute Womens Heatlh, England.
    Ghoussaini, Maya
    University of Cambridge, England.
    Giles, Graham G.
    Cancer Council Victoria, Australia; University of Melbourne, Australia.
    Glasspool, Rosalind
    Beatson West Scotland Cancer Centre, Scotland.
    Godwin, Andrew K.
    University of Kansas, KS 66160 USA.
    Goldberg, Mark S.
    McGill University, Canada; McGill University, Canada.
    Goldgar, David E.
    University of Utah, UT 84132 USA.
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre, Spain.
    Goode, Ellen L.
    Mayo Clin, MN 55902 USA.
    Goodman, Marc T.
    Cedars Sinai Medical Centre, CA 90048 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Greene, Mark H.
    NCI, MD 20892 USA.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Guenel, Pascal
    INSERM, France; University of Paris 11, France.
    Haiman, Christopher A.
    University of Southern Calif, CA 90033 USA.
    Hall, Per
    Karolinska Institute, Sweden.
    Hallberg, Emily
    Mayo Clin, MN 55902 USA.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Harrington, Patricia A.
    University of Cambridge, England.
    Hartman, Mikael
    National University of Health Syst, Singapore; National University of Singapore, Singapore.
    Hassan, Norhashimah
    University of Malaya, Malaysia; Cancer Research Initiat Fdn, Malaysia.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Heitz, Florian
    Kliniken Essen Mitte, Germany; Dr Horst Schmidt Kliniken Wiesbaden, Germany.
    Herzog, Josef
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Hogdall, Estrid
    University of Copenhagen, Denmark; Danish Cancer Soc Research Centre, Denmark.
    Hogdall, Claus K.
    University of Copenhagen, Denmark.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Hollestelle, Antoinette
    Erasmus MC Cancer Institute, Netherlands.
    Hopper, John L.
    University of Melbourne, Australia.
    Hulick, Peter J.
    NorthShore University of Health Syst, IL 60201 USA.
    Huzarski, Tomasz
    Pomeranian Medical University, Poland.
    Imyanitov, Evgeny N.
    NN Petrov Institute Oncol, Russia.
    Isaacs, Claudine
    Georgetown University, DC 20057 USA.
    Ito, Hidemi
    Aichi Cancer Centre, Japan.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Janavicius, Ramunas
    Centre Innovat Med, Lithuania.
    Jensen, Allan
    University of Copenhagen, Denmark.
    John, Esther M.
    Cancer Prevent Institute Calif, CA 94538 USA.
    Johnson, Nichola
    Institute Cancer Research, England.
    Kabisch, Maria
    German Cancer Research Centre, Germany.
    Kang, Daehee
    Seoul National University, South Korea.
    Kapuscinski, Miroslav
    University of Melbourne, Australia.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Khan, Sofia
    University of Helsinki, Finland.
    Kiemeney, Lambertus A.
    Radboud University of Nijmegen, Netherlands.
    Kruger Kjaer, Susanne
    Danish Cancer Soc Research Centre, Denmark; University of Copenhagen, Denmark.
    Knight, Julia A.
    Lunenfeld Tanenbaum Research Institute Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Konstantopoulou, Irene
    Aghia Paraskevi Attikis, Greece.
    Kosma, Veli-Matti
    Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Kristensen, Vessela
    Oslo University Hospital, Norway; University of Oslo, Norway; University of Oslo, Norway.
    Kupryjanczyk, Jolanta
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Kwong, Ava
    Hong Kong Sanat and Hospital, Peoples R China; University of Hong Kong, Peoples R China.
    de la Hoya, Miguel
    IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Lambrechts, Diether
    VIB, Belgium; University of Leuven, Belgium.
    Le, Nhu
    University of Southern Calif, CA 90033 USA.
    De Leeneer, Kim
    University of Ghent, Belgium.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Levine, Douglas A.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Li, Jingmei
    Karolinska Institute, Sweden.
    Lindblom, Annika
    Karolinska Institute, Sweden.
    Long, Jirong
    Vanderbilt University, TN 37203 USA.
    Lophatananon, Artitaya
    University of Warwick, England.
    Loud, Jennifer T.
    NCI, MD 20892 USA.
    Lu, Karen
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Mannermaa, Arto
    Kuopio University Hospital, Finland; Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Manoukian, Siranoush
    Ist Nazl Tumori, Italy.
    Le Marchand, Loic
    University of Hawaii, HI 96813 USA.
    Margolin, Sara
    Karolinska Institute, Sweden.
    Marme, Frederik
    Heidelberg University, Germany; Heidelberg University, Germany.
    Massuger, Leon F. A. G.
    Radboud University of Nijmegen, Netherlands.
    Matsuo, Keitaro
    Kyushu University, Japan.
    Mazoyer, Sylvie
    University of Lyon, France.
    McGuffog, Lesley
    University of Cambridge, England.
    McLean, Catriona
    Alfred Hospital, Australia.
    McNeish, Iain
    University of Glasgow, Scotland.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Menon, Usha
    UCL EGA Institute Womens Heatlh, England.
    Mensenkamp, Arjen R.
    Radboud University of Nijmegen, Netherlands.
    Milne, Roger L.
    Cancer Council Victoria, Australia; University of Melbourne, Australia.
    Montagna, Marco
    IRCCS, Italy.
    Moysich, Kirsten B.
    Roswell Pk Cancer Institute, NY 14263 USA.
    Muir, Kenneth
    University of Warwick, England; University of Manchester, England.
    Mulligan, Anna Marie
    University of Health Network, Canada; University of Toronto, Canada.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Ness, Roberta B.
    University of Texas Houston, TX 77030 USA.
    Neuhausen, Susan L.
    Beckman Research Institute City Hope, CA 91010 USA.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Nord, Silje
    University of Oslo, Norway.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA 94143 USA.
    Odunsi, Kunle
    Roswell Pk Cancer Institute, NY 14263 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Olson, Janet E.
    Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
    Olswold, Curtis
    Mayo Clin, MN 55902 USA.
    OMalley, David
    Ohio State University, OH 43210 USA; James Graham Brown Cancer Centre, OH 43210 USA.
    Orlow, Irene
    Mem Sloan Kettering Cancer Centre, NY 10017 USA.
    Orr, Nick
    Institute Cancer Research, England.
    Osorio, Ana
    University of Copenhagen, Denmark; Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease CIBERER, Spain.
    Kyung Park, Sue
    Seoul National University, South Korea; Seoul National University, South Korea; Seoul National University, South Korea.
    Pearce, Celeste L.
    University of Southern Calif, CA 90033 USA.
    Pejovic, Tanja
    Oregon Health and Science University, OR 97239 USA; Oregon Health and Science University, OR 97239 USA.
    Peterlongo, Paolo
    FIRC Italian Fdn Cancer Research, Italy.
    Pfeiler, Georg
    Medical University of Vienna, Austria.
    Phelan, Catherine M.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33606 USA.
    Poole, Elizabeth M.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Pylkas, Katri
    Centre NordLab, Finland; University of Oulu, Finland.
    Radice, Paolo
    Ist Nazl Tumori, Italy.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Usman Rashid, Muhammad
    German Cancer Research Centre, Germany; Shaukat Khanum Mem Cancer Hospital and Research Centre SKMCH and RC, Pakistan.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel.
    Rhenius, Valerie
    University of Cambridge, England.
    Rhiem, Kerstin
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Risch, Harvey A.
    Yale University, CT 06510 USA.
    Rodriguez, Gus
    NorthShore University of HealthSyst, IL 60201 USA.
    Anne Rossing, Mary
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98109 USA.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Salvesen, Helga B.
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Sangrajrang, Suleeporn
    National Cancer Institute, Thailand.
    Sawyer, Elinor J.
    Kings Coll London, England.
    Schildkraut, Joellen M.
    Duke University, NC 27710 USA; Duke Cancer Institute, NC 27710 USA.
    Schmidt, Marjanka K.
    Netherlands Cancer Institute, Netherlands.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Sellers, Thomas A.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33606 USA.
    Seynaeve, Caroline
    Erasmus MC Cancer Institute, Netherlands.
    Shah, Mitul
    University of Cambridge, England.
    Shen, Chen-Yang
    Academic Sinica, Taiwan; China Medical University, Taiwan.
    Shu, Xiao-Ou
    Vanderbilt University, TN 37203 USA.
    Sieh, Weiva
    Stanford University, CA 94305 USA.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Sinilnikova, Olga M.
    Centre Leon Berard, France; University of Lyon 1, France.
    Slager, Susan
    Mayo Clin, MN 55902 USA.
    Song, Honglin
    University of Cambridge, England.
    Soucy, Penny
    University of Laval, Canada.
    Southey, Melissa C.
    University of Melbourne, Australia.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. University of Lund Hospital, Sweden.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; Institute Curie, France; Sorbonne Paris Cite, France.
    Sutter, Christian
    University of Heidelberg Hospital, Germany.
    Swerdlow, Anthony
    Institute Cancer Research, England; Institute Cancer Research, England.
    Tchatchou, Sandrine
    Mt Sinai Hospital, Canada.
    Teixeira, Manuel R.
    Portuguese Oncology Institute, Portugal; University of Porto, Portugal.
    Teo, Soo H.
    University of Malaya, Malaysia; Cancer Research Initiat Fdn, Malaysia.
    Terry, Kathryn L.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Beth Terry, Mary
    Columbia University, NY 10027 USA.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Grazia Tibiletti, Maria
    University of Insubria, Italy.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Tognazzo, Silvia
    IRCCS, Italy.
    Ewart Toland, Amanda
    Vanderbilt University, TN 37203 USA; IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain; Ohio State University, OH 43210 USA.
    Tomlinson, Ian
    University of Oxford, England; University of Oxford, England.
    Torres, Diana
    German Cancer Research Centre, Germany; Pontificia University of Javeriana, Colombia.
    Truong, Therese
    INSERM, France; University of Paris 11, France.
    Tseng, Chiu-chen
    University of Southern Calif, CA 90033 USA.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Tworoger, Shelley S.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Vachon, Celine
    Mayo Clin, MN 55902 USA.
    van den Ouweland, Ans M. W.
    Erasmus University, Netherlands.
    van Doorn, Helena C.
    Erasmus MC Cancer Institute, Netherlands.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Vant Veer, Laura J.
    Netherlands Cancer Institute, Netherlands.
    Vanderstichele, Adriaan
    University Hospital Leuven, Belgium.
    Vergote, Ignace
    University Hospital Leuven, Belgium.
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Wang, Qin
    University of Cambridge, England.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Wentzensen, Nicolas
    NCI, MD 20892 USA.
    Whittemore, Alice S.
    Stanford University, CA 94305 USA.
    Wildiers, Hans
    University Hospital Leuven, Belgium.
    Winqvist, Robert
    Centre NordLab, Finland; University of Oulu, Finland.
    Wu, Anna H.
    University of Southern Calif, CA 90033 USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece.
    Yoon, Sook-Yee
    Sime Darby Medical Centre, Malaysia; University of Malaya, Malaysia.
    Yu, Jyh-Cherng
    National Def Medical Centre, Taiwan.
    Zheng, Wei
    Vanderbilt University, TN 37203 USA.
    Zheng, Ying
    Shanghai Centre Disease Control and Prevent, Peoples R China.
    Kum Khanna, Kum
    QIMR Berghofer Medical Research Institute, Australia.
    Simard, Jacques
    University of Laval, Canada.
    Monteiro, Alvaro N.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33612 USA.
    French, Juliet D.
    QIMR Berghofer Medical Research Institute, Australia.
    Couch, Fergus J.
    Mayo Clin, MN 55902 USA; Mayo Clin, MN 55905 USA.
    Freedman, Matthew L.
    Dana Farber Cancer Institute, MA 02215 USA.
    Easton, Douglas F.
    University of Cambridge, England; University of Cambridge, England.
    Dunning, Alison M.
    University of Cambridge, England.
    Pharoah, Paul D.
    University of Cambridge, England.
    Edwards, Stacey L.
    QIMR Berghofer Medical Research Institute, Australia.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Gayther, Simon A.
    University of Southern Calif, CA 90033 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12675Article in journal (Refereed)
    Abstract [en]

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

  • 19.
    Martrat, Griselda
    et al.
    IDIBELL.
    Maxwell, Christopher A.
    IDIBELL.
    Tominaga, Emiko
    University of Texas Health Science Centre San Antonio.
    Porta-de-la-Riva, Montserrat
    Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, IDIBELL, Spain.
    Bonifaci, Nuria
    IDIBELL.
    Gomez-Baldo, Laia
    IDIBELL.
    Bogliolo, Massimo
    Autonomous University Barcelona.
    Lazaro, Conxi
    IDIBELL.
    Blanco, Ignacio
    IDIBELL.
    Brunet, Joan
    Hospital Josep Trueta.
    Aguilar, Helena
    Bellvitge Institute Biomed Research IDIBELL.
    Fernandez-Rodriguez, Juana
    IDIBELL.
    Seal, Sheila
    Institute Canc Research.
    Renwick, Anthony
    Institute Canc Research.
    Rahman, Nazneen
    Institute Canc Research.
    Küehl, Julia
    Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, Würzburg, Germany .
    Neveling, Kornelia
    University Wurzburg.
    Schindler, Detlev
    University Wurzbur.
    J. Ramirez, Maria
    Autonomous University Barcelona.
    Castella, Maria
    Autonomous University Barcelon.
    Hernandez, Gonzalo
    Autonomous University Barcelona.
    F. Easton, Douglas
    University Cambridge.
    Peock, Susan
    University Cambridge.
    Cook, Margaret
    University Cambridge.
    T. Oliver, Clare
    University Cambridge.
    Frost, Debra
    University Cambridge.
    Platte, Radka
    University Cambridge.
    Gareth Evans, D.
    Cent Manchester University Hospital NHS Fdn Trust.
    Lalloo, Fiona
    Cent Manchester University Hospital NHS Fdn Trust.
    Eeles, Rosalind
    Institute Canc Research, Oncogenet Team.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust.
    Chu, Carol
    St James Hospital.
    Davidson, Rosemarie
    Ferguson Smith Centre Clin Genet.
    Ong, Kai-Ren
    Birmingham Womens Hospital Healthcare NHS Trust.
    Cook, Jackie
    Sheffield Childrens Hospital.
    Douglas, Fiona
    Newcastle Upon Tyne Hospital NHS Trust.
    Hodgson, Shirley
    University London.
    Brewer, Carole
    Royal Devon and Exeter Hospital.
    J. Morrison, Patrick
    Belfast City Hospital.
    Porteous, Mary
    Western Gen Hospital.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Manoukian, Siranoush
    Fdn IRCCS INT.
    Peissel, Bernard
    Fdn IRCCS INT.
    Zaffaroni, Daniela
    Fdn IRCCS INT.
    Roversi, Gaia
    Fdn IRCCS INT.
    Barile, Monica
    Ist Europeo Oncol IEO.
    Viel, Alessandra
    IRCCS.
    Pasini, Barbara
    University Turin.
    Ottini, Laura
    University Roma La Sapienza.
    Laura Putignano, Anna
    Fiorgen Fdn Pharmacogen.
    Savarese, Antonella
    Regina Elena Institute Canc Research.
    Bernard, Loris
    IEO.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Healey, Sue
    Queensland Institute Med Research.
    Spurdle, Amanda
    Queensland Institute Med Research.
    Chen, Xiaoqing
    Queensland Institute Med Research.
    Beesley, Jonathan
    Queensland Institute Med Research.
    A. Rookus, Matti
    Netherlands Canc Institute.
    Verhoef, Senno
    Netherlands Canc Institute.
    A. Tilanus-Linthorst, Madeleine
    Erasmus MC Daniel den Hoed Canc Centre.
    P. Vreeswijk, Maaike
    Leiden University.
    J. Asperen, Christi
    Leiden University.
    Bodmer, Danielle
    Radboud University Nijmegen.
    G. E. M. Ausems, Margreet
    University Med Centre Utrecht.
    A. van Os, Theo
    University Amsterdam.
    J. Blok, Marinus
    University Hospital Maastricht.
    E. J. Meijers-Heijboer, Hanne
    Vrije University Amsterdam Med Centre.
    B. L. Hogervorst, Frans
    Netherlands Canc Institute.
    E. Goldgar, David
    University Utah.
    Buys, Saundra
    Huntsman Canc Institute.
    M. John, Esther
    Canc Prevent Institute Calif.
    Miron, Alexander
    Harvard University.
    Southey, Melissa
    University Melbourne.
    B. Daly, Mary
    Fox Chase Canc Centre.
    Harbst, Katja
    Skane University Hospital.
    Borg, Ake
    Skane University Hospital.
    Rantala, Johanna
    Karolinska University Hospital.
    Barbany-Bustinza, Gisela
    Karolinska University Hospital.
    Ehrencrona, Hans
    Uppsala University.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Kaufman, Bella
    The Institute of Oncology, Chaim Sheba Medical Center, Israel .
    Laitman, Yael
    Chaim Sheba Med Centre.
    Milgrom, Roni
    Chaim Sheba Med Centre.
    Friedman, Eitan
    Chaim Sheba Med Centre.
    M. Domchek, Susan
    University Penn.
    L. Nathanson, Katherine
    University Penn.
    R. Rebbeck, Timothy
    University Penn.
    Thor Johannsson, Oskar
    Department of Oncology, 20A Landspitali-LSH v/Hringbraut, Reykjavik, Iceland.
    J. Couch, Fergus
    Mayo Clin.
    Wang, Xianshu
    Mayo Clin.
    Fredericksen, Zachary
    Mayo Clin.
    Cuadras, Daniel
    IDIBELL.
    Moreno, Vctor
    IDIBELL.
    K. Pientka, Friederike
    University Lubeck.
    Depping, Reinhard
    University Lubeck.
    Caldes, Trinidad
    Hospital Clin San Carlos.
    Osorio, Ana
    Spanish Natl Canc Research Centre.
    Benitez, Javier
    Spanish Natl Canc Research Centre.
    Bueren, Juan
    Centre Invest Energet Medioambientales and Tecnol CIEM,.
    Heikkinen, Tuomas
    University Helsinki.
    Nevanlinna, Heli
    University Helsinki.
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ.
    Torres, Diana
    Pontificia University Javeriana.
    Adelaide Caligo, Maria
    University Hospital Pisa.
    K. Godwin, Andrew
    University Kansas.
    N. Imyanitov, Evgeny
    NN Petrov Oncol Research Institute.
    Janavicius, Ramunas
    Vilnius University Hospital.
    M. Sinilnikova, Olga
    University Lyon 1.
    Stoppa-Lyonnet, Dominique
    Institute Curie.
    Mazoyer, Sylvie
    University Lyon 1.
    Verny-Pierre, Carole
    University Lyon 1.
    Castera, Laurent
    Institute Curie.
    de Pauw, Antoine
    Institute Curie.
    Bignon, Yves-Jean
    University Clermont Ferrand.
    Uhrhammer, Nancy
    University Clermont Ferrand.
    Peyrat, Jean-Philippe
    Centre Oscar Lambret.
    Vennin, Philippe
    Consultation d'Oncogénétique, Centre Oscar Lambret, Lille, France .
    Fert Ferrer, Sandra
    Hotel Dieu Centre Hospital.
    Collonge-Rame, Marie-Agnes
    CHU Besancon.
    Mortemousque, Isabelle
    CHU Bretonneau.
    McGuffog, Lesley
    University Cambridge.
    Chenevix-Trench, Georgia
    Queensland Institute Med Research.
    M. Pereira-Smith, Olivia
    University Texas Hlth Science Centre San Antonio.
    C. Antoniou, Antonis
    University Cambridge.
    Ceron, Julian
    IDIBELL.
    Tominaga, Kaoru
    University Texas Hlth Science Centre San Antonio.
    Surralles, Jordi
    Autonomous University Barcelona.
    Angel Pujana, Miguel
    Catalan Institute of Oncology, IDIBELL, Spain.
    Exploring the link between MORF4L1 and risk of breast cancer2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 2Article in journal (Refereed)
    Abstract [en]

    Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

  • 20.
    Mosrati, Mohamed Ali
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Lysiak, Malgorzata
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Krysztofiak, Adam
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Bratthall, Charlotte
    Dist Hospital, Sweden.
    Strandeus, Michael
    Ryhov Hospital, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 18, p. 16663-16673Article in journal (Refereed)
    Abstract [en]

    Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNPs, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.

  • 21.
    Mulligan, Anna Marie
    et al.
    University of Toronto.
    Couch, Fergus J
    Rochester.
    Barrowdale, Daniel
    University of Cambridge.
    Domchek, Susan M
    University of Penn.
    Eccles, Diana
    University of Southampton.
    Nevanlinna, Heli
    University of Helsinki.
    Ramus, Susan J
    University of So Calif.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre.
    Sherman, Mark
    NCI.
    Spurdle, Amanda B
    Queensland Institute Medical Research.
    Wappenschmidt, Barbara
    University Hospital Cologne.
    Lee, Andrew
    University of Cambridge.
    McGuffog, Lesley
    University of Cambridge.
    Healey, Sue
    Queensland Institute Medical Research.
    Sinilnikova, Olga M
    Centre Hospital University of Lyon Centre Leon Berard.
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin.
    Hansen, Thomas V O
    Copenhagen University Hospital.
    Nielsen, Finn C
    Copenhagen University Hospital.
    Ejlertsen, Bent
    Copenhagen University Hospital, Rigshosp.
    Osorio, Ana
    Spanish National Cancer Research Centre.
    Munoz-Repeto, Ivan
    Spanish National Cancer Research Centre.
    Duran, Mercedes
    University of Valladolid.
    Godino, Javier
    Hospital Clin University of Lozano Blesa.
    Pertesi, Maroulio
    National Centre Science Research Demokritos.
    Benitez, Javier
    Spanish National Cancer Research Centre.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumouri INT.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumouri INT.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumouri INT.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumouri INT.
    Cattaneo, Elisa
    Fdn IRCCS Ist Nazl Tumouri INT.
    Bonanni, Bernardo
    Ist Europeo Oncol, Div Cancer Prevent and Genet.
    Viel, Alessandra
    IRCCS.
    Pasini, Barbara
    University of Turin.
    Papi, Laura
    University of Florence.
    Ottini, Laura
    University of Roma La Sapienza.
    Savarese, Antonella
    Regina Elena Institute Cancer Research.
    Bernard, Loris
    Ist Europeo Oncol.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumouri INT.
    Hamann, Ute
    DKFZ.
    Verheus, Martijn
    Netherlands Cancer Institute.
    Meijers-Heijboer, Hanne E J
    Vrije University of Amsterdam Medical Centre.
    Wijnen, Juul
    Leiden University.
    Gomez Garcia, EncarnaB
    MUMC.
    Nelen, Marcel R
    Radboud University of Nijmegen.
    Kets, C Marleen
    Radboud University of Nijmegen.
    Seynaeve, Caroline
    Erasmus University.
    Tilanus-Linthorst, Madeleine M A
    Erasmus University.
    van der Luijt, Rob B
    University of Medical Centre Utrecht.
    van Os, Theo
    University of Amsterdam.
    Rookus, Matti
    Netherlands Cancer Institute.
    Frost, Debra
    University of Cambridge.
    Jones, J Louise
    Queen Mary University of London.
    Evans, D Gareth
    Central Manchester University Hospital NHS Fdn Trust.
    Lalloo, Fiona
    Central Manchester University Hospital NHS Fdn Trust.
    Eeles, Ros
    Institute Cancer Research, Oncogenet Team, London.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust.
    Adlard, Julian
    Yorkshire Regional Genet Serv.
    Davidson, Rosemarie
    Yorkhill Hospital.
    Cook, Jackie
    Sheffield Childrens Hospital.
    Donaldson, Alan
    St Michaels Hospital.
    Dorkins, Huw
    Kennedy Galton Centre.
    Gregory, Helen
    NHS Grampian.
    Eason, Jacqueline
    Nottingham University Hospital NHS Trust.
    Houghton, Catherine
    Liverpool Womens NHS Fdn Trust.
    Barwell, Julian
    University Hospital Leicester NHS Trust.
    E Side, Lucy
    Great Ormond St Hospital Sick Children.
    McCann, Emma
    Glan Clwyd Gen Hospital.
    Murray, Alex
    Singleton Hospital.
    Peock, Susan
    University of Cambridge.
    K Godwin, Andrew
    University of Kansas.
    K Schmutzler, Rita
    University Hospital Cologne.
    Rhiem, Kerstin
    University Hospital Cologne.
    Engel, Christoph
    University of Leipzig.
    Meindl, Alfons
    Technical University of Munich.
    Ruehl, Ina
    University of Munich.
    Arnold, Norbert
    University of Kiel.
    Niederacher, Dieter
    University of Dusseldorf.
    Sutter, Christian
    University of Heidelberg Hospital.
    Deissler, Helmut
    University Hospital.
    Gadzicki, Dorothea
    Hannover Medical Sch.
    Kast, Karin
    Technical University of Dresden.
    Preisler-Adams, Sabine
    University of Munster.
    Varon-Mateeva, Raymonda
    Charite, Campus Virchov Klinikum.
    Schoenbuchner, Ines
    University of Wurzburg.
    Fiebig, Britta
    University of Regensburg.
    Heinritz, Wolfram
    University of Leipzig.
    Schaefer, Dieter
    University Hospital, Frankfurt.
    Gevensleben, Heidrun
    Institute Cancer Research,London.
    Caux-Moncoutier, Virginie
    Institute Curie .
    Fassy-Colcombet, Marion
    Institute Curie.
    Cornelis, Francois
    Avicenne Hospital.
    Mazoyer, Sylvie
    University of Lyon 1.
    Leone, Melanie
    Centre Hospital University of Lyon Centre Leon Berard.
    Boutry-Kryza, Nadia
    Centre Hospital University of Lyon Centre Leon Berard.
    Hardouin, Agnes
    Centre Francois Baclesse.
    Berthet, Pascaline
    Centre Francois Baclesse.
    Muller, Daniele
    CLCC Paul Strauss.
    Fricker, Jean-Pierre
    CLCC Paul Strauss.
    Mortemousque, Isabelle
    CHU Bretonneau.
    Pujol, Pascal
    CHU Amaud de Villeneuve.
    Coupier, Isabelle
    CHU Amaud de Villeneuve.
    Lebrun, Marine
    Centre Hospital University of St Etienne.
    Kientz, Caroline
    Centre Hospital University of St Etienne.
    Longy, Michel
    University of Bordeaux.
    Sevenet, Nicolas
    University of Bordeaux.
    Stoppa-Lyonnet, Dominique
    Institute Curie.
    Isaacs, Claudine
    Georgetown University.
    Caldes, Trinidad
    Hospital Clin San Carlos.
    de la Hoya, Miguel
    Hospital Clin San Carlos.
    Heikkinen, Tuomas
    University of Helsinki.
    Aittomaki, Kristiina
    University of Helsinki.
    Blanco, Ignacio
    Hospital Duran i Reynals Bellvitge Biomed Research Institute ID.
    Lazaro, Conxi
    Hospital Duran i Reynals Bellvitge Biomed Research Institute ID.
    B Barkardottir, Rosa
    Landspitali University Hospital.
    Soucy, Penny
    CHU Quebec.
    Dumont, Martine
    CHU Quebec.
    Simard, Jacques
    CHU Quebec.
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS.
    Tognazzo, Silvia
    Ist Oncology Veneto IOV IRCCS.
    DAndrea, Emma
    University of Padua.
    Fox, Stephen
    Peter MacCallum Cancer Centre.
    Yan, Max
    Prince Wales Hospital.
    Rebbeck, Tim
    Abramson Cancer Centre.
    I Olopade, Olufunmilayo
    University of Chicago.
    N Weitzel, Jeffrey
    City Hope National Medical Centre.
    T Lynch, Henry
    Creighton University.
    A Ganz, Patricia
    University of Calif Los Angeles.
    E Tomlinson, Gail
    University of Texas SW Medical Centre Dallas.
    Wang, Xianshu
    Mayo Clin.
    Fredericksen, Zachary
    Mayo Clin.
    S Pankratz, Vernon
    Mayo Clin.
    M Lindor, Noralane
    Mayo Clin.
    Szabo, Csilla
    University of Delaware.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre.
    Sakr, Rita
    Mem Sloan Kettering Cancer Centre.
    Gaudet, Mia
    Amer Cancer Soc.
    Bhatia, Jasmine
    Mem Sloan Kettering Cancer Centre.
    Kauff, Noah
    Mem Sloan Kettering Cancer Centre.
    F Singer, Christian
    Medical University of Vienna.
    Tea, Muy-Kheng
    Medical University of Vienna.
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna.
    Fink-Retter, Anneliese
    Medical University of Vienna.
    L Mai, Phuong
    US National Cancer Institute.
    H Greene, Mark
    US National Cancer Institute.
    Imyanitov, Evgeny
    NN Petrov Institute Oncol.
    P OMalley, Frances
    St Michaels Hospital.
    Ozcelik, Hilmi
    Mt Sinai Hospital.
    Glendon, Gordon
    Ohio State University.
    Gerdes, Anne-Marie
    University of Copenhagen.
    Thomassen, Mads
    Odense University Hospital.
    A Kruse, Torben
    Odense University Hospital.
    Birk Jensen, Uffe
    Aarhus University Hospital.
    Skytte, Anne-Bine
    Vejle Hospital.
    A Caligo, Maria
    University of Pisa.
    Soller, Maria
    University of Lund Hospital.
    Henriksson, Karin
    University of Lund Hospital.
    Anna Wachenfeldt, von
    Karolinska University Hospital.
    Arver, Brita
    Karolinska University Hospital.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Karlsson, Per
    Sahlgrens University Hospital.
    Chun Ding, Yuan
    City Hope National Medical Centre.
    L Neuhausen, Susan
    City Hope National Medical Centre.
    Beattie, Mary
    University of Calif San Francisco.
    D P Pharoah, Paul
    University of Cambridge.
    B Moysich, Kirsten
    Roswell Pk Cancer Institute.
    L Nathanson, Katherine
    University of Penn.
    Y Karlan, Beth
    Cedars Sinai Medical Centre.
    Gross, Jenny
    Cedars Sinai Medical Centre.
    M John, Esther
    Cancer Prevent Institute Calif.
    B Daly, Mary
    Fox Chase Cancer Centre.
    M Buys, Saundra
    University of Utah.
    C Southey, Melissa
    University of Melbourne.
    L Hopper, John
    University of Melbourne.
    Beth Terry, Mary
    Columbia University.
    Chung, Wendy
    Columbia University.
    F Miron, Alexander
    Dana Farber Cancer Institute.
    Goldgar, David
    University of Utah.
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research.
    F Easton, Douglas
    University of Cambridge.
    L Andrulis, Irene
    University of Toronto.
    C Antoniou, Antonis
    University of Cambridge.
    Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/22011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 6Article in journal (Refereed)
    Abstract [en]

    Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. less thanbrgreater than less thanbrgreater thanMethods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. less thanbrgreater than less thanbrgreater thanResults: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. less thanbrgreater than less thanbrgreater thanConclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

  • 22.
    Osorio, A
    et al.
    Spanish National Cancer Centre.
    Milne, R L
    Spanish National Cancer Centre.
    Alonso, R
    Spanish National Cancer Centre.
    Pita, G
    Spanish National Cancer Centre.
    Peterlongo, P
    Fdn IRCCS Ist Nazl Tumori.
    Teule, A
    Catalan Institute of Oncology.
    Nathanson, K L
    University of Pennsylvania.
    Domchek, S M
    University of Pennsylvania.
    Rebbeck, T
    University of Pennsylvania.
    Lasa, A
    Hospital Santa Creu and Sant Pau.
    Konstantopoulou, I
    NCSR Demokritos.
    Hogervorst, F B
    Netherlands Cancer Institute.
    Verhoef, S
    Netherlands Cancer Institute.
    van Dooren, M F
    Erasmus University.
    Jager, A
    Erasmus University.
    Ausems, M G E M
    University Medical Centre Utrecht.
    Aalfs, C M
    University of Amsterdam.
    van Asperen, C J
    Leiden University.
    Vreeswijk, M
    Leiden University.
    Waisfisz, Q
    Vrije University Amsterdam.
    Van Roozendaal, C E
    University Medical Centre.
    Ligtenberg, M J
    Radboud University Nijmegen.
    Easton, D F
    University of Cambridge.
    Peock, S
    University of Cambridge.
    Cook, M
    University of Cambridge.
    Oliver, C T
    University of Cambridge.
    Frost, D
    University of Cambridge.
    Curzon, B
    University of Cambridge.
    Evans, D G
    Central Manchester University Hospital.
    Lalloo, F
    Central Manchester University Hospital.
    Eeles, R
    Institute for Cancer Research and Royal Marsden.
    Izatt, L
    Guys and St Thomas.
    Davidson, R
    Yorkhill Hospital.
    Adlard, J
    Yorkshire Reg Genet Serv.
    Eccles, D
    Princess Anne Hospital.
    Ong, K-R
    Birmingham Womens Hospital.
    Douglas, F
    Newcastle Upon Tyne Hospital.
    Downing, S
    Addenbrookes Hospital.
    Brewer, C
    Royal Devon and Exeter Hospital.
    Walker, L
    Churchill Hospital.
    Nevanlinna, H
    University of Helsinki.
    Aittomaki, K
    Mayo Clinic.
    Fredericksen, Z
    Mayo Clinic.
    Lindor, N M
    Mayo Clinic.
    Godwin, A
    University of Kansas.
    Isaacs, C
    MD Georgetown University.
    Caligo, M A
    University and University Hospital Pisa.
    Loman, N
    University of Lund Hospital.
    Jernstrom, H
    University of Lund Hospital.
    Barbany-Bustinza, G
    Karolinska University Hospital.
    Liljegren, A
    Karolinska University Hospital.
    Ehrencrona, H
    Uppsala University.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Feliubadalo, L
    Catalan Institute of Oncology.
    Manoukian, S
    Fdn IRCCS Ist Nazl Tumori.
    Peissel, B
    Fdn IRCCS Ist Nazl Tumori.
    Zaffaroni, D
    Fdn IRCCS Ist Nazl Tumori.
    Bonanni, B
    Ist Europeo Oncology.
    Fortuzzi, S
    Cogentech.
    Johannsson, O T
    University of Iceland.
    Chenevix-Trench, G
    Queensland Institute Medical Research.
    Chen, X-C
    Queensland Institute Medical Research.
    Beesley, J
    Queensland Institute Medical Research.
    B Spurdle, A
    Queensland Institute Medical Research.
    Sinilnikova, O M
    Centre Hospital University Lyon.
    Healey, S
    Queensland Institute Med Research.
    McGuffog, L
    University of Cambridge.
    Antoniou, A C
    University of Cambridge.
    Brunet, J
    Catalan Institute of Oncololgy.
    Radice, P
    Fdn IRCCS Ist Nazl Tumori.
    Benitez, J
    Spanish National Cancer Centre.
    Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA22011In: BRITISH JOURNAL OF CANCER, ISSN 0007-0920, Vol. 104, no 8, p. 1356-1361Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77Candgt;T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, Pandlt;0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

  • 23.
    Osorio, A.
    et al.
    Spanish Natl Canc Res Ctr, Human Genet Grp, Madrid, Spain.
    Milne, R L
    Spanish Natl Canc Res Ctr, Genet and Mol Epidemiol Grp, Madrid, Spain.
    Pita, G.
    Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain.
    Peterlongo, P.
    Fdn IRCCS Ist Nazl Tumori, Milan, Italy.
    Heikkinen, T.
    Helsinki Univ Cent Hosp, Dept Obstet and Gynaecol, Helsvinki, Finland.
    Simard, J.
    Ctr Hosp Univ Quebec, Canc Genom Lab, Canada Res Chair Oncogenet, Quebec City, PQ, Canada.
    Chenevix-Trench, G.
    Queensland Inst Med Res, Div Genet and Populat Hlth, Brisbane, Qld 4006, Australia.
    Spurdle, A B
    Queensland Inst Med Res, Div Genet and Populat Hlth, Brisbane, Qld 4006, Australia.
    Beesley, J.
    Queensland Inst Med Res, Div Genet and Populat Hlth, Brisbane, Qld 4006, Australia.
    Chen, X.
    Queensland Inst Med Res, Div Genet and Populat Hlth, Brisbane, Qld 4006, Australia.
    Healey, S.
    Queensland Inst Med Res, Div Genet and Populat Hlth, Brisbane, Qld 4006, Australia.
    Neuhausen, S L
    Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA.
    Ding, Y C
    Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA.
    Couch, F J
    Mayo Clin, Dept Lab Med and Pathol, Rochester, MN USA.
    Wang, X.
    Mayo Clin, Dept Lab Med and Pathol, Rochester, MN USA.
    Lindor, N.
    Mayo Clin, Dept Med Genet, Rochester, MN USA.
    Manoukian, S.
    Fdn IRCCS Ist Nazl Tumori, Milan, Italy.
    Barile, M.
    Ist Europeo Oncol, Milan, Italy.
    Viel, A.
    IRCCS, Ctr Riferimento Oncol, Aviano, PN, Italy.
    Tizzoni, L.
    Fdn Ist FIRC Oncol Mol, Milan, Italy.
    Szabo, C I
    Mayo Clin, Coll Med, Dept Lab Med and Pathol, Rochester, MN USA.
    Foretova, L.
    Masaryk Mem Canc Inst, Dept Canc Epidemiol and Genet, Brno, Czech Republic.
    Zikan, M.
    Charles Univ Prague, Fac Med 1, Dept Biochem and Expt Oncol, Prague, Czech Republic.
    Claes, K.
    Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium.
    Greene, M H
    NCI, Clin Genet Branch, Rockville, MD USA.
    Mai, P.
    NCI, Clin Genet Branch, Rockville, MD USA.
    Rennert, G.
    Carmel Hosp, CHS Natl Canc Control Ctr, Haifa, Israel.
    Lejbkowicz, F.
    Carmel Hosp, CHS Natl Canc Control Ctr, Haifa, Israel.
    Barnett-Griness, O.
    Carmel Hosp, CHS Natl Canc Control Ctr, Haifa, Israel.
    Andrulis, I L
    Ontario Canc Genet Network, Toronto, ON, Canada.
    Ozcelik, H.
    Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada.
    Weerasooriya, N.
    Ontario Canc Genet Network, Toronto, ON, Canada.
    Gerdes, A-M
    Odense Univ Hosp, Clin Genet BFG, DK-5000 Odense, Denmark.
    Thomassen, M.
    Odense Univ Hosp, Clin Genet BFG, DK-5000 Odense, Denmark.
    Cruger, D G
    Vejle Hosp, Dept Clin Genet, Vijle, Denmark.
    Caligo, M A
    Univ Pisa, Dept Oncol, Div Pathol, Pisa, Italy.
    Friedman, E.
    Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel.
    Kaufman, B.
    Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel.
    Laitman, Y.
    Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel.
    Cohen, S.
    Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel.
    Kontorovich, T.
    Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel.
    Gershoni-Baruch, R.
    Rambam Med Ctr, Haifa, Israel.
    Dagan, E.
    Univ Haifa, Fac Social Welf and Hlth Sci, Dept Nursing, IL-31999 Haifa, Israel.
    Jernstrom, H.
    Lund Univ, Dept Oncol, Lund, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Arver, B.
    Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden.
    Malmer, B.
    Umea Univ, Dept Radiat Sci, Umea, Sweden.
    Domchek, S M
    Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA.
    Nathanson, K L
    Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA.
    Brunet, J.
    Hosp Dr Josep Trueta IdiBGi, Inst Catalan Oncol, Programa Consejo Genet Canc, Girona, Spain.
    Cajal, T. Ramon y
    Hosp Santa Creu and Sant Pau, Med Oncol Serv, Barcelona, Spain.
    Yannoukakos, D.
    Demokritos Natl Ctr Sci Res, IRRP, Mol Diagnost Lab, GR-15310 Athens, Greece.
    Hamann, U.
    Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany.
    Hogervorst, F B L
    Netherlands Canc Inst, Family Canc Clin, Dept Clin Mol Genet, Amsterdam, Netherlands.
    Verhoef, S.
    Netherlands Canc Inst, Family Canc Clin, Dept Clin Mol Genet, Amsterdam, Netherlands.
    Gomez Garcia, E B
    Univ Med Ctr, Dept Genet and Cell Biol, Maastricht, Netherlands.
    Wijnen, J T
    Leiden Univ, Med Ctr, Dept Clin Mol Genet, Leiden, Netherlands.
    van den Ouweland, A.
    Erasmus Univ, Med Ctr, Dept Mol Genet, Rotterdam, Netherlands.
    Easton, D F
    Univ Cambridge, Dept Publ Hlth and Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England.
    Peock, S.
    Univ Cambridge, Dept Publ Hlth and Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England.
    Cook, M.
    Univ Cambridge, Dept Publ Hlth and Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England.
    Oliver, C T
    Univ Cambridge, Dept Publ Hlth and Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England.
    Frost, D.
    Univ Cambridge, Dept Publ Hlth and Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England.
    Luccarini, C.
    Univ Cambridge, Dept Oncol, Cambridge, England.
    Evans, D G
    St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England.
    Lalloo, F.
    St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England.
    Eeles, R.
    Inst Canc Res, Translat Canc Genet Team, London SW3 6JB, England.
    Pichert, G.
    Guys Hosp, London SE1 9RT, England.
    Cook, J.
    Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England.
    Hodgson, S.
    Univ London, St Georges Hosp, Dept Canc Genet, London, England.
    Morrison, P J
    Belfast City Hosp, No Ireland Reg Genet Ctr, Belfast BT9 7AD, Antrim, North Ireland.
    Douglas, F.
    Newcastle Upon Tyne Hosp NHS Trust, Inst Human Genet, Ctr Life, Newcastle Upon Tyne, Tyne and Wear, England.
    Godwin, A K
    Fox Chase Canc Ctr, Philadelphia, PA 19111 USA.
    Sinilnikova, O M
    Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France.
    Barjhoux, L.
    Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France.
    Stoppa-Lyonnet, D.
    Univ Paris 05, Inst Curie, Serv Gent Oncol, INSERM,U509, Paris, France.
    Moncoutier, V.
    Univ Paris 05, Inst Curie, Serv Gent Oncol, INSERM,U509, Paris, France.
    Giraud, S.
    Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France.
    Cassini, C.
    Ctr Genet, Dijon, France.
    Olivier-Faivre, L.
    Ctr Genet, Dijon, France.
    Revillion, F.
    Ctr Oscar Lambret, Human Mol Oncol Lab, F-59020 Lille, France.
    Peyrat, J-P
    Ctr Oscar Lambret, Human Mol Oncol Lab, F-59020 Lille, France.
    Muller, D.
    CLCC Paul Strauss, Unite Oncogenet, Strasbourg, France.
    Fricker, J-P
    CLCC Paul Strauss, Unite Oncogenet, Strasbourg, France.
    Lynch, H T
    Creighton Univ, Dept Prevent Med, Omaha, NE 68178 USA.
    John, E M
    No Calif Canc Ctr, Fremont, CA USA.
    Buys, S.
    Huntsman Canc Inst, Salt Lake City, UT USA.
    Daly, M.
    Fox Chase Canc Ctr, Philadelphia, PA 19111 USA.
    Hopper, J L
    Univ Melbourne, Melbourne, Vic, Australia.
    Terry, M B
    Columbia Univ, New York, NY USA.
    Miron, A.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Yassin, Y.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Goldgar, D.
    Univ Utah, Dept Dermatol, Salt Lake City, UT USA.
    Singer, C F
    Med Univ Vienna, Dept OB GYN, Div Special Gynecol, Vienna, Austria.
    Gschwantler-Kaulich, D.
    Med Univ Vienna, Dept OB GYN, Div Special Gynecol, Vienna, Austria.
    Pfeiler, G.
    Med Univ Vienna, Dept OB GYN, Div Special Gynecol, Vienna, Austria.
    Spiess, A-C
    Med Univ Vienna, Dept OB GYN, Div Special Gynecol, Vienna, Austria.
    v. O. Hansen, Thomas
    Odense Univ Hosp, Dept Biochem Pharmacol and Genet, DK-5000 Odense, Denmark.
    T. Johannsson, O.
    Landspitali Univ Hosp, Dept Oncol, Reykjavik, Iceland.
    Kirchhoff, T.
    Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA.
    Offit, K.
    Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA.
    Kosarin, K.
    Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA.
    Piedmonte, M.
    Roswell Pk Canc Inst, GOG Stat and Data Ctr, Buffalo, NY 14263 USA.
    C. Rodriguez, G.
    Evanston NW Healthcare, NorthShore Univ Hlth Syst, Evanston, IL USA.
    Wakeley, K.
    Tufts Univ, New England Med Ctr, Boston, MA 02111 USA.
    F. Boggess, J.
    Univ N Carolina, Chapel Hill, NC USA.
    Basil, J.
    St Elizabeth Hosp, Edgewood, KY USA.
    E. Schwartz, P.
    Yale Univ, Sch Med, New Haven, CT USA.
    V. Blank, S.
    NYU, Sch Med, New York, NY USA.
    E. Toland, A.
    Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Dept Internal Med and Mol Virol, Columbus, OH 43210 USA.
    Montagna, M.
    IRCCS, Inst Oncol Veneto, Padua, Italy.
    Casella, C.
    Dept Oncol and Surg Sci, Padua, Italy.
    N. Imyanitov, E.
    NN Petrov Oncol Res Inst, St Petersburg, Russia.
    Allavena, A.
    Univ Turin, Dept Genet Biol and Biochem, Turin, Italy.
    K. Schmutzler, R.
    Univ Cologne, Dept Obstet and Gynaecol, Div Mol Gynaecooncol, Cologne, Germany.
    Versmold, B.
    Univ Cologne, Dept Obstet and Gynaecol, Div Mol Gynaecooncol, Cologne, Germany.
    Engel, C.
    Univ Leipzig, Inst Med Informat Stat and Epidemiol, Leipzig, Germany.
    Meindl, A.
    Tech Univ Munich, Dept Obstet and Gynaecol, Munich, Germany.
    Ditsch, N.
    Univ Munich, Dept Obstet and Gynaecol, Munich, Germany.
    Arnold, N.
    Univ Schleswig Holstein, Dept Obstet and Gynaecol, Lubeck, Germany.
    Niederacher, D.
    Univ Dusseldorf, Dept Obstet and Gynaecol, Mol Genet Lab, Dusseldorf, Germany.
    Deissler, H.
    Univ Ulm, Dept Obstet and Gynaecol, Ulm, Germany.
    Fiebig, B.
    Univ Regensburg, Inst Human Genet, Regensburg, Germany.
    Varon-Mateeva, R.
    Humboldt Univ, Inst Human Genet, Charite, Berlin, Germany.
    Schaefer, D.
    Goethe Univ Frankfurt, Inst Human Genet, Frankfurt, Germany.
    G. Froster, U.
    Univ Leipzig, Inst Human Genet, Leipzig, Germany.
    Caldes, T.
    Hosp Clin San Carlos, Madrid, Spain.
    de la Hoya, M.
    Hosp Clin San Carlos, Madrid, Spain.
    McGuffog, L.
    Univ Cambridge, Dept Publ Hlth and Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England.
    C. Antoniou, A.
    Univ Cambridge, Dept Publ Hlth and Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England.
    Nevanlinna, H.
    Helsinki Univ Cent Hosp, Dept Obstet and Gynaecol, Helsvinki, Finland.
    Radice, P.
    Fdn IRCCS Ist Nazl Tumori, Milan, Italy.
    Benitez, J.
    Spanish Natl Canc Res Ctr, Human Genet Grp, Madrid, Spain.
    Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, no 12, p. 2048-2054Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron I of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

  • 24.
    Peterlongo, Paolo
    et al.
    Fdn Ist FIRC Oncology Molecolare, Italy; Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany.
    Moysich, Kirsten B.
    Roswell Pk Cancer Institute, NY 14263 USA.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University of Cologne, Germany.
    Simard, Jacques
    Centre Hospital University of Quebec Research Centre, Canada; University of Laval, Canada.
    Soucy, Penny
    Centre Hospital University of Quebec Research Centre, Canada; University of Laval, Canada.
    Eeles, Rosalind A.
    Institute Cancer Research, England; Royal Marsden NHS Fdn Trust, England.
    Easton, Douglas F.
    University of Cambridge, England.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Wilkening, Stefan
    German Cancer Research Centre, Germany.
    Chen, Bowang
    German Cancer Research Centre, Germany.
    Rookus, Matti A.
    Netherlands Cancer Institute, Netherlands.
    Schmidt, MarjankaK.
    Netherlands Cancer Institute, Netherlands.
    van der Baan, Frederieke H.
    Netherlands Cancer Institute, Netherlands.
    Spurdle, Amanda B.
    QIMR Berghofer, Australia.
    Walker, Logan C.
    University of Otago, New Zealand; Churchill Hospital, England.
    Lose, Felicity
    QIMR Berghofer, Australia.
    Maia, Ana-Teresa
    University of Algarve, Portugal.
    Montagna, Marco
    IRCCS, Italy.
    Matricardi, Laura
    IRCCS, Italy.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Gomez Garcia, Encarna B.
    MUMC, Netherlands.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA USA; University of Calif San Francisco, CA 94143 USA.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Rebbeck, Timothy R.
    University of Penn, PA 19104 USA.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Orsulic, Sandra
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Chung, Wendy K.
    Columbia University, NY 10027 USA; Columbia University, NY USA.
    Miron, Alex
    Case Western Reserve Medical Sch, OH USA.
    Southey, Melissa C.
    University of Melbourne, Australia.
    Goldgar, David E.
    University of Utah, UT USA.
    Buys, Saundra S.
    University of Utah, UT USA.
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin, Lithuania; State Research Institute Centre Innovat Med, Lithuania.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Chun Ding, Yuan
    Beckman Research Institute City Hope, CA USA.
    Neuhausen, Susan L.
    Beckman Research Institute City Hope, CA USA.
    Hansen, Thomas V. O.
    University of Copenhagen Hospital, Denmark.
    Gerdes, Anne-Marie
    University of Copenhagen Hospital, Denmark.
    Ejlertsen, Bent
    University of Copenhagen Hospital, Denmark.
    Jonson, Lars
    University of Copenhagen Hospital, Denmark.
    Osorio, Ana
    Biomed Network Rare Disease CIBERER, Spain; Spanish National Cancer Centre CNIO, Spain.
    Martinez-Bouzas, Cristina
    Cruces Hospital Barakaldo, Spain.
    Benitez, Javier
    Biomed Network Rare Disease CIBERER, Spain; Spanish National Cancer Centre CNIO, Spain; Spanish National Cancer Centre CNIO, Spain.
    Conway, Edye E.
    City Hope Clin Cancer Genet Community Research Network, CA USA.
    Blazer, Kathleen R.
    City Hope National Medical Centre, CA USA.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA USA.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Scuvera, Giulietta
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Ficarazzi, Filomena
    Fdn Ist FIRC Oncology Molecolare, Italy; Cogentech Cancer Genet Test Lab, Italy.
    Mariette, Frederique
    Fdn Ist FIRC Oncology Molecolare, Italy; Cogentech Cancer Genet Test Lab, Italy.
    Fortuzzi, Stefano
    Fdn Ist FIRC Oncology Molecolare, Italy; Cogentech Cancer Genet Test Lab, Italy.
    Viel, Alessandra
    CRO Aviano National Cancer Institute, Italy.
    Giannini, Giuseppe
    University of Roma La Sapienza, Italy.
    Papi, Laura
    University of Florence, Italy.
    Martayan, Aline
    Ist Nazl Tumori Regina Elena, Italy.
    Grazia Tibiletti, Maria
    Polo University of Varese, Italy.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Vratimos, Athanassios
    National Centre Science Research Demokritos, Greece.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Garber, Judy E.
    Dana Farber Cancer Institute, MA 02115 USA.
    Donaldson, Alan
    St Michaels Hospital, England.
    Brewer, Carole
    Royal Devon and Exeter Hospital, England.
    Foo, Claire
    Liverpool Womens NHS Fdn Trust, England.
    Evans, D. Gareth R.
    Central Manchester University Hospital NHS Fdn Trust, England.
    Frost, Debra
    University of Cambridge, England.
    Eccles, Diana
    University of Southampton, England.
    Brady, Angela
    Kennedy Galton Centre, England.
    Cook, Jackie
    Sheffield Childrens Hospital, England.
    Tischkowitz, Marc
    Addenbrookes Hospital, England.
    Adlard, Julian
    Yorkshire Regional Genet Serv, England.
    Barwell, Julian
    University Hospital Leicester NHS Trust, England.
    Walker, Lisa
    University of Otago, New Zealand; Churchill Hospital, England.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust, England.
    Side, Lucy E.
    Great Ormond St Hospital Sick Children, England.
    John Kennedy, M.
    University of Dublin Trinity Coll, Ireland; St James Hospital, Ireland.
    Rogers, Mark T.
    University of Wales Hospital, Wales.
    Porteous, Mary E.
    Western Gen Hospital, Scotland.
    Morrison, Patrick J.
    Queens University of Belfast, North Ireland.
    Platte, Radka
    University of Cambridge, England.
    Davidson, Rosemarie
    So Gen Hospital, Scotland.
    Hodgson, Shirley V.
    St Georges University of London, England.
    Ellis, Steve
    University of Cambridge, England.
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, England.
    Godwin, Andrew K.
    University of Kansas, MO USA.
    Claes, Kathleen
    University of Ghent, Belgium.
    Van Maerken, Tom
    University of Ghent, Belgium.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Gehrig, Andrea
    University of Wurzburg, Germany.
    Sutter, Christian
    Heidelberg University, Germany.
    Engel, Christoph
    University of Leipzig, Germany.
    Niederacher, Dieter
    University of Dusseldorf, Germany.
    Steinemann, Doris
    Hannover Medical Sch, Germany.
    Plendl, Hansjoerg
    University of Kiel, Germany.
    Kast, Karin
    Technical University of Dresden, Germany.
    Rhiem, Kerstin
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University of Cologne, Germany.
    Ditsch, Nina
    University of Munich, Germany.
    Arnold, Norbert
    University of Kiel, Germany.
    Varon-Mateeva, Raymonda
    Charite, Germany.
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University of Cologne, Germany.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Bressac-de Paillerets, Brigitte
    Fdn Jean Dausset, France; Institute Cancerol Gustave Roussy, France.
    Buecher, Bruno
    Institute Curie, France.
    Delnatte, Capucine
    Centre Rene Gauducheau, France.
    Houdayer, Claude
    Institute Curie, France; University of Paris 05, France.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; University of Paris 05, France; INSERM U830, France.
    Damiola, Francesca
    University of Lyon 1, France.
    Coupier, Isabelle
    CHU Arnaud Villeneuve, France; CRLCC Val Aurelle, France.
    Barjhoux, Laure
    CRLCC Val Aurelle, France.
    Venat-Bouvet, Laurence
    Centre Hospital University of Dupuytren, France.
    Golmard, Lisa
    Institute Curie, France.
    Boutry-Kryza, Nadia
    Hospital Civils Lyon, France.
    Sinilnikova, Olga M.
    University of Lyon 1, France; Hospital Civils Lyon, France.
    Caron, Olivier
    Institute Cancerol Gustave Roussy, France.
    Pujol, Pascal
    CHU Arnaud Villeneuve, France; INSERM 896, France.
    Mazoyer, Sylvie
    University of Lyon 1, France.
    Belotti, Muriel
    Institute Curie, France.
    Piedmonte, Marion
    Roswell Pk Cancer Institute, NY 14263 USA.
    Friedlander, Michael L.
    Australia New Zealand Gynaecol Oncology Grp, Australia.
    Rodriguez, Gustavo C.
    NorthShore University of HealthSyst, IL USA.
    Copeland, Larry J.
    Ohio State University, OH USA.
    de la Hoya, Miguel
    Hospital Clin San Carlos, Spain.
    Perez Segura, Pedro
    Hospital Clin San Carlos, Spain.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Aittomaeki, Kristiina
    University of Helsinki, Finland.
    van Os, Theo A. M.
    University of Amsterdam, Netherlands.
    Meijers-Heijboer, Hanne E. J.
    Vrije University of Amsterdam Medical Centre, Netherlands.
    van der Hout, Annemarie H.
    University of Groningen, Netherlands.
    Vreeswijk, Maaike P. G.
    Leiden University, Netherlands.
    Hoogerbrugge, Nicoline
    Radboud University of Nijmegen, Netherlands.
    Ausems, Margreet G. E. M.
    University of Medical Centre Utrecht, Netherlands.
    van Doorn, Helena C.
    Erasmus University, Netherlands.
    Margriet Collee, J.
    Erasmus University, Netherlands.
    Olah, Edith
    National Institute Oncol, Hungary.
    Diez, Orland
    University Hospital Vall Hebron, Spain; University of Autonoma Barcelona, Spain; Vall Hebron Institute Oncol, Spain; Vall Hebron Research Institute, Spain.
    Blanco, Ignacio
    IDIBELL Catalan Institute Oncol, Spain.
    Lazaro, Conxi
    IDIBELL Catalan Institute Oncol, Spain.
    Brunet, Joan
    IDIBGI Catalan Institute Oncol, Spain.
    Feliubadalo, Lidia
    University of Iceland, Iceland.
    Cybulski, Cezary
    Pomeranian Medical University, Poland.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Durda, Katarzyna
    Pomeranian Medical University, Poland.
    Jaworska-Bieniek, Katarzyna
    Pomeranian Medical University, Poland.
    Sukiennicki, Grzegorz
    Pomeranian Medical University, Poland.
    Arason, Adalgeir
    University of Iceland, Iceland; Landspitali University Hospital, Iceland.
    Chiquette, Jocelyne
    University of Quebec, Canada.
    Teixeira, Manuel R.
    University of Porto, Portugal; Portuguese Oncology Institute, Portugal.
    Olswold, Curtis
    Mayo Clin, NY USA.
    Couch, Fergus J.
    Mayo Clin, NY USA.
    Lindor, Noralane M.
    Mayo Clin, AZ USA.
    Wang, Xianshu
    Mayo Clin, NY USA.
    Szabo, Csilla I.
    NIH, MD 20892 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Corines, Marina
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Jacobs, Lauren
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Robson, Mark E.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Zhang, Liying
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Joseph, Vijai
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Berger, Andreas
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Singer, Christian F.
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Rappaport, Christine
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Geschwantler Kaulich, Daphne
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Pfeiler, Georg
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Tea, Muy-Kheng M.
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Phelan, Catherine M.
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Greene, Mark H.
    NIH, MD USA.
    Mai, Phuong L.
    NIH, MD USA.
    Rennert, Gad
    Clalit National Cancer Control Centre, Israel.
    Marie Mulligan, Anna
    University of Toronto, Canada; University of Health Network, Canada.
    Glendon, Gord
    Mt Sinai Hospital, Canada.
    Tchatchou, Sandrine
    Mt Sinai Hospital, Canada.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; Ohio State University, OH 43210 USA.
    Ewart Toland, Amanda
    Ohio State University, OH 43210 USA; Ohio State University, OH 43210 USA.
    Bojesen, Anders
    Vejle Hospital, Denmark.
    Sokilde Pedersen, Inge
    Aalborg University Hospital, Denmark.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    Laitman, Yael
    Sheba Medical Centre, Israel.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    von Wachenfeldt, Anna
    Karolinska University Hospital, Sweden.
    Ehrencrona, Hans
    University of Lund Hospital, Sweden; Uppsala University, Sweden.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Borg, Ake
    Lund University, Sweden.
    Kuchenbaecker, Karoline B.
    University of Cambridge, England.
    McGuffog, Lesley
    University of Cambridge, England.
    Barrowdale, Daniel
    University of Cambridge, England.
    Healey, Sue
    QIMR Berghofer, Australia.
    Lee, Andrew
    University of Cambridge, England.
    Pharoah, Paul D. P.
    University of Cambridge, England.
    Chenevix-Trench, Georgia
    QIMR Berghofer, Australia.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Friedman, Eitan
    Sheba Medical Center, Israel.
    Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers2015In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 1, p. 308-316Article in journal (Refereed)
    Abstract [en]

    Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

  • 25. Ramus, Susan J
    et al.
    Antoniou, Antonis C
    Kuchenbaecker, Karoline B
    Soucy, Penny
    Beesley, Jonathan
    Chen, Xiaoqing
    McGuffog, Lesley
    Sinilnikova, Olga M
    Healey, Sue
    Barrowdale, Daniel
    Lee, Andrew
    Thomassen, Mads
    Gerdes, Anne-Marie
    Kruse, Torben A
    Jensen, Uffe Birk
    Skytte, Anne-Bine
    Caligo, Maria A
    Liljegren, Annelie
    Lindblom, Annika
    Olsson, Håkan
    Kristoffersson, Ulf
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Domchek, Susan M
    Nathanson, Katherine L
    Rebbeck, Timothy R
    Jakubowska, Anna
    Lubinski, Jan
    Jaworska, Katarzyna
    Durda, Katarzyna
    Złowocka, Elżbieta
    Gronwald, Jacek
    Huzarski, Tomasz
    Byrski, Tomasz
    Cybulski, Cezary
    Toloczko-Grabarek, Aleksandra
    Osorio, Ana
    Benitez, Javier
    Duran, Mercedes
    Tejada, Maria-Isabel
    Hamann, Ute
    Rookus, Matti
    van Leeuwen, Flora E
    Aalfs, Cora M
    Meijers-Heijboer, Hanne E J
    van Asperen, Christi J
    van Roozendaal, K E P
    Hoogerbrugge, Nicoline
    Collée, J Margriet
    Kriege, Mieke
    van der Luijt, Rob B
    Peock, Susan
    Frost, Debra
    Ellis, Steve D
    Platte, Radka
    Fineberg, Elena
    Evans, D Gareth
    Lalloo, Fiona
    Jacobs, Chris
    Eeles, Ros
    Adlard, Julian
    Davidson, Rosemarie
    Eccles, Diana
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Douglas, Fiona
    Brewer, Carole
    Hodgson, Shirley
    Morrison, Patrick J
    Walker, Lisa
    Porteous, Mary E
    Kennedy, M John
    Pathak, Harsh
    Godwin, Andrew K
    Stoppa-Lyonnet, Dominique
    Caux-Moncoutier, Virginie
    de Pauw, Antoine
    Gauthier-Villars, Marion
    Mazoyer, Sylvie
    Léoné, Mélanie
    Calender, Alain
    Lasset, Christine
    Bonadona, Valérie
    Hardouin, Agnès
    Berthet, Pascaline
    Bignon, Yves-Jean
    Uhrhammer, Nancy
    Faivre, Laurence
    Loustalot, Catherine
    Buys, Saundra
    Daly, Mary
    Miron, Alex
    Terry, Mary Beth
    Chung, Wendy K
    John, Esther M
    Southey, Melissa
    Goldgar, David
    Singer, Christian F
    Tea, Muy-Kheng
    Pfeiler, Georg
    Fink-Retter, Anneliese
    Hansen, Thomas v O
    Ejlertsen, Bent
    Johannsson, Oskar Th
    Offit, Kenneth
    Kirchhoff, Tomas
    Gaudet, Mia M
    Vijai, Joseph
    Robson, Mark
    Piedmonte, Marion
    Phillips, Kelly-Anne
    Van Le, Linda
    Hoffman, James S
    Ewart Toland, Amanda
    Montagna, Marco
    Tognazzo, Silvia
    Imyanitov, Evgeny
    Issacs, Claudine
    Janavicius, Ramunas
    Lazaro, Conxi
    Blanco, Iganacio
    Tornero, Eva
    Navarro, Matilde
    Moysich, Kirsten B
    Karlan, Beth Y
    Gross, Jenny
    Olah, Edith
    Vaszko, Tibor
    Teo, Soo-Hwang
    Ganz, Patricia A
    Beattie, Mary S
    Dorfling, Cecelia M
    van Rensburg, Elizabeth J
    Diez, Orland
    Kwong, Ava
    Schmutzler, Rita K
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Ditsch, Nina
    Arnold, Norbert
    Heidemann, Simone
    Niederacher, Dieter
    Preisler-Adams, Sabine
    Gadzicki, Dorotehea
    Varon-Mateeva, Raymonda
    Deissler, Helmut
    Gehrig, Andrea
    Sutter, Christian
    Kast, Karin
    Fiebig, Britta
    Schäfer, Dieter
    Caldes, Trinidad
    de la Hoya, Miguel
    Nevanlinna, Heli
    Aittomäki, Kristiina
    Plante, Marie
    Spurdle, Amanda B
    Neuhausen, Susan L
    Ding, Yuan Chun
    Wang, Xianshu
    Lindor, Noralane
    Fredericksen, Zachary
    Pankratz, V Shane
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Bonanni, Bernardo
    Bernard, Loris
    Dolcetti, Riccardo
    Papi, Laura
    Ottini, Laura
    Radice, Paolo
    Greene, Mark H
    Mai, Phuong L
    Andrulis, Irene L
    Glendon, Gord
    Ozcelik, Hilmi
    Pharoah, Paul D P
    Gayther, Simon A
    Simard, Jacques
    Easton, Douglas F
    Couch, Fergus J
    Chenevix-Trench, Georgia
    Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.2012In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, no 4, p. 690-702Article in journal (Refereed)
    Abstract [en]

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

  • 26.
    Ramus, Susan J
    et al.
    UCL.
    Kartsonaki, Christiana
    University Cambridge, Department Publ Hlth and Primary Care, Centre Canc Genet Epidemiol, Cambridge, England .
    A Gayther, Simon
    UCL, Department Gynaecol Oncol, UCL EGA Institute Womens Hlth, London, England .
    D P Pharoah, Paul
    University Cambridge, Strangeways Research Lab, Canc Research United Kingdom Department Oncol, Cambridge, England University Cambridge, Strangeways Research Lab, Department Publ Hlth and Primary Care, Cambridge, England .
    M Sinilnikova, Olga
    University Lyon, Centre Hospital University Lyon, Centre Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France University Lyon, CNRS, Centre Leon Berard, UMR5201,Equipe Labellisee LIGUE 2008, Lyon, France .
    Beesley, Jonathan
    Queensland Institute Med Research, Brisbane, Qld 4006 Australia .
    Chen, Xiaoqing
    Queensland Institute Med Research, Brisbane, Qld 4006 Australia .
    McGuffog, Lesley
    University Cambridge, Department Publ Hlth and Primary Care, Centre Canc Genet Epidemiol, Cambridge, England .
    Healey, Sue
    Queensland Institute Med Research, Brisbane, Qld 4006 Australia University London, St Georges Hospital, Department Clin Genet, London, England .
    J Couch, Fergus
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA .
    Wang, Xianshu
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA .
    Fredericksen, Zachary
    Mayo Clin, Department Hlth Science Research, Rochester, MN USA .
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Department Expt Oncol and Mol Med, Unit Genet Susceptibil Canc, Milan, Italy Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy .
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Department Prevent and Predict Med, Unit Med Genet, Milan, Italy University Lyon, Centre Leon Berard, CNRS, Equipe Labellisee LIGUE 2008,UMR5201, Lyon, France .
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Department Prevent and Predict Med, Unit Med Genet, Milan, Italy .
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumori INT, Department Prevent and Predict Med, Unit Med Genet, Milan, Italy .
    Roversi, Gaia
    Fdn IRCCS Ist Nazl Tumori INT, Department Prevent and Predict Med, Unit Med Genet, Milan, Italy .
    Barile, Monica
    IEO, Div Canc Prevent and Genet, Milan, Italy .
    Viel, Alessandra
    IRCCS, Div Expt Oncol 1, CRO, Aviano, PN Italy .
    Allavena, Anna
    University Turin, Department Genet Biol and Biochem, Turin, Italy .
    Ottini, Laura
    University Roma La Sapienza, Department Expt Med, I-00185 Rome, Italy .
    Papi, Laura
    University Florence, Department Clin Physiopathol, Med Genet Unit, Florence, Italy .
    Gismondi, Viviana
    IRCCS Ist Nazl Ric Canc IST, Department Epidemiol and Prevent, Genoa, Italy .
    Capra, Fabio
    Cogentech, Consortium Genom Technology, Milan, Italy .
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Department Expt Oncol and Mol Med, Unit Genet Susceptibil Canc, Milan, Italy Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy .
    H Greene, Mark
    NCI, Div Canc Epidemiol and Genet, Clin Genet Branch, Bethesda, MD 20892 USA .
    L Mai, Phuong
    NCI, Div Canc Epidemiol and Genet, Clin Genet Branch, Bethesda, MD 20892 USA .
    L Andrulis, Irene
    Ontario Canc Genet Network, Toronto, ON Canada Mt Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, ON M5G 1X5 Canada .
    Glendon, Gord
    Ontario Canc Genet Network, Toronto, ON Canada .
    Ozcelik, Hilmi
    Mt Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, ON M5G 1X5 Canada Lund University, Department Oncol, Lund, Sweden .
    Thomassen, Mads
    Odense University Hospital, DK-5000 Odense, Denmark .
    Gerdes, Anne-Marie
    Odense University Hospital, DK-5000 Odense, Denmark Rigshosp, DK-2100 Copenhagen, Denmark .
    A Kruse, Torben
    Odense University Hospital, DK-5000 Odense, Denmark .
    Cruger, Dorthe
    Vejle Hospital, Vejle, Denmark .
    Birk Jensen, Uffe
    Aarhus University Hospital, DK-8000 Aarhus, Denmark .
    Adelaide Caligo, Maria
    University Hospital Pisa, Department Oncol, Sect Genet Oncol, Pisa, Italy .
    Olsson, Hakan
    Lund University, Department Clin Genet, Lund, Sweden .
    Lindblom, Annika
    Karolinska University Hospital, Department Clin Genet, Stockholm, Sweden .
    Arver, Brita
    Karolinska University Hospital, Department Oncol, Stockholm, Sweden .
    Karlsson, Per
    Sahlgrens University Hospital, Department Oncol, Gothenburg, Sweden .
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Borg, Ake
    Lund University, Department Oncol, Lund, Sweden .
    L Neuhausen, Susan
    City Hope Natl Med Centre, Beckman Research Institute, Department Populat Science, Duarte, CA USA .
    Chun Ding, Yuan
    City Hope Natl Med Centre, Beckman Research Institute, Department Populat Science, Duarte, CA USA .
    L Nathanson, Katherine
    University Penn, Sch Med, Department Med, Philadelphia, PA 19104 USA University Penn, Sch Med, Abramson Canc Centre, Philadelphia, PA 19104 USA .
    M Domchek, Susan
    University Penn, Sch Med, Department Med, Philadelphia, PA 19104 USA University Penn, Sch Med, Abramson Canc Centre, Philadelphia, PA 19104 USA .
    Jakubowska, Anna
    Pomeranian Med University, Department Genet and Pathol, Int Hereditary Canc Centre, Szczecin, Poland .
    Lubinski, Jan
    Pomeranian Med University, Department Genet and Pathol, Int Hereditary Canc Centre, Szczecin, Poland .
    Huzarski, Tomasz
    Pomeranian Med University, Department Genet and Pathol, Int Hereditary Canc Centre, Szczecin, Poland .
    Byrski, Tomasz
    Pomeranian Med University, Department Genet and Pathol, Int Hereditary Canc Centre, Szczecin, Poland .
    Gronwald, Jacek
    Pomeranian Med University, Department Genet and Pathol, Int Hereditary Canc Centre, Szczecin, Poland Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA USA .
    Gorski, Bohdan
    Pomeranian Med University, Department Genet and Pathol, Int Hereditary Canc Centre, Szczecin, Poland .
    Cybulski, Cezary
    Pomeranian Med University, Department Genet and Pathol, Int Hereditary Canc Centre, Szczecin, Poland .
    Debniak, Tadeusz
    Pomeranian Med University, Department Genet and Pathol, Int Hereditary Canc Centre, Szczecin, Poland .
    Osorio, Ana
    University Valladolid, Institute Biol and Mol Genet IBGM UVA, Valladolid, Spain .
    Tejada, Maria-Isabel
    Cruces Hospital Barakaldo, Mol Genet Lab, Department Biochem, Bizkaia, Spain .
    Benitez, Javier
    Spanish Natl Canc Research Centre, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain Spanish Natl Canc Research Centre, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain .
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ, Heidelberg, Germany .
    A Rookus, Matti
    Netherlands Canc Institute, Department Epidemiol, Amsterdam, Netherlands .
    Verhoef, Senno
    Netherlands Canc Institute, Family Canc Clin, Amsterdam, Netherlands .
    A Tilanus-Linthorst, Madeleine
    Erasmus MC Daniel den Hoed Canc Centre, Family Canc Clin, Department Surg Oncol, Rotterdam, Netherlands .
    P Vreeswijk, Maaike
    Leiden University, Med Centre, Centre Human and Clin Genet, Leiden, Netherlands .
    Bodmer, Danielle
    Radboud University Nijmegen, Med Centre, Department Human Genet, NL-6525 ED Nijmegen, Netherlands .
    G E M Ausems, Margreet
    University Med Centre Utrecht, Department Med Genet, Utrecht, Netherlands .
    A van Os, Theo
    University Amsterdam, Acad Med Centre, Department Clin Genet, NL-1105 AZ Amsterdam, Netherlands .
    J Asperen, Christi
    Leiden University, Med Centre, Centre Human and Clin Genet, Leiden, Netherlands .
    J Blok, Marinus
    University Hospital Maastricht, Department Clin Genet, Maastricht, Netherlands .
    E J Meijers-Heijboer, Hanne
    Vrije University Amsterdam Med Centre, Department Clin Genet, Amsterdam, Netherlands .
    Peock, Susan
    University Cambridge, Department Publ Hlth and Primary Care, Centre Canc Genet Epidemiol, Cambridge, England .
    Cook, Margaret
    University Cambridge, Department Publ Hlth and Primary Care, Centre Canc Genet Epidemiol, Cambridge, England .
    Oliver, Clare
    University Cambridge, Department Publ Hlth and Primary Care, Centre Canc Genet Epidemiol, Cambridge, England .
    Frost, Debra
    University Cambridge, Department Publ Hlth and Primary Care, Centre Canc Genet Epidemiol, Cambridge, England .
    M Dunning, Alison
    University Cambridge, Centre Canc Genet Epidemiol, Department Oncol, Cambridge, England .
    Gareth Evans, D
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs England .
    Eeles, Ros
    Guys and St Thomas NHS Fdn Trust, London, England .
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands England Hospital San Carlos, Mol Oncol Lab, Madrid, Spain .
    Hodgson, Shirley
    Royal Devon and Exeter Hospital, Department Clin Genet, Exeter EX2 5DW, Devon England .
    J Morrison, Patrick
    Belfast City Hospital, No Ireland Reg Genet Centre, Belfast BT9 7AD, Antrim North Ireland .
    Porteous, Mary
    Western Gen Hospital, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian Scotland .
    John Kennedy, M
    Trinity Coll Dublin, Acad Unit Clin and Mol Oncol, Dublin, Eire Ireland St James Hospital, Dublin, Eire Ireland .
    T Rogers, Mark
    University Wales Hospital, All Wales Med Genet Serv, Cardiff CF4 4XW, S Glam Wales .
    E Side, Lucy
    Great Ormond St Hospital Sick Children, NE Thames Reg Genet Serv, London WC1N 3JH, England .
    Donaldson, Alan
    St Michaels Hospital, Department Clin Genet, Bristol, Avon England .
    Gregory, Helen
    NHS Grampian, N Scotland Reg Genet Serv, Aberdeen, Scotland University Aberdeen, Aberdeen, Scotland .
    Godwin, Andrew
    University Paris 05, Institute Curie, INSERM, Serv Genet Oncol,U509, Paris, France .
    Moncoutier, Virginie
    University Paris 05, Institute Curie, INSERM, Serv Genet Oncol,U509, Paris, France .
    Castera, Laurent
    University Paris 05, Institute Curie, INSERM, Serv Genet Oncol,U509, Paris, France .
    Mazoyer, Sylvie
    University Lyon, Centre Leon Berard, CNRS, Equipe Labellisee LIGUE 2008,UMR5201, Lyon, France .
    Bonadona, Valerie
    Centre Leon Berard, Unite Prevent and Epidemiol Genet, F-69373 Lyon, France University Lyon 1, CNRS, UMR5558, Lyon, France .
    Leroux, Dominique
    CHU Grenoble, Department Genet, F-38043 Grenoble, France University Grenoble, Institute Albert Bonniot, Grenoble, France .
    Faivre, Laurence
    Centre Hospital University Dijon, Centre Genet, Dijon, France Centre Lutte Canc Georges Francois Leclerc, Dijon, France .
    Lidereau, Rosette
    INSERM, U735, Centre Rene Huguenin, St Cloud, France .
    Nogues, Catherine
    Centre Rene Huguenin, Epidemiol Clin, St Cloud, France .
    Bignon, Yves-Jean
    Centre Jean Perrin, Department Oncogenet, Clermont Ferrand, France .
    Prieur, Fabienne
    Centre Hospital University St Etienne, Serv Genet Clin Chromosom and Mol, St Etienne, France .
    Collonge-Rame, Marie-Agnes
    CHU Besancon, Serv Genet Histol Biol Dev and Reprod, F-25030 Besancon, France .
    Venat-Bouvet, Laurence
    Centre Hospital University Dupuytren, Department Med Oncol, Limoges, France .
    Fert-Ferrer, Sandra
    Hotel Dieu Centre Hospital, Lab Genet Chromosom, Chambery, France .
    Miron, Alex
    Dana Farber Canc Institute, Department Canc Biol, Womens Cancers Program, Boston, MA 02115 USA Tech University Munich, Klinikum Rechts Isar, Div Tumor Genet, Department Obstet and Gynaecol, D-8000 Munich, Germany .
    S Buys, Saundra
    University Utah, Hlth Science Centre, Huntsman Canc Institute, Salt Lake City, UT USA .
    L Hopper, John
    University Melbourne, Melbourne Sch Populat Hlth, Centre Mol Environm Genet and Analyt Epidemiol, Melbourne, Vic Australia .
    B Daly, Mary
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA .
    M John, Esther
    Canc Prevent Institute Calif, Fremont, CA USA Stanford University, Sch Med, Stanford, CA 94305 USA .
    Beth Terry, Mary
    Columbia University, Joseph L Mailman Sch Publ Hlth, Department Epidemiol, New York, NY 10027 USA .
    Goldgar, David
    University Utah, Department Dermatol, Salt Lake City, UT 84112 USA .
    V O Hansen, Thomas
    Copenhagen University Hospital, Rigshosp, Department Clin Biochem, Copenhagen, Denmark .
    Jonson, Lars
    Copenhagen University Hospital, Rigshosp, Department Clin Biochem, Copenhagen, Denmark .
    Ejlertsen, Bent
    Copenhagen University Hospital, Rigshosp, Department Oncol, Copenhagen, Denmark .
    A Agnarsson, Bjarni
    University Hospital, Department Pathol, Reykjavik, Iceland University Iceland, Sch Med, Reykjavik, Iceland .
    Offit, Kenneth
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA .
    Kirchhoff, Tomas
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA .
    Vijai, Joseph
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA .
    V C Dutra-Clarke, Ana
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA .
    A Przybylo, Jennifer
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA .
    Montagna, Marco
    Ist Oncol Veneto IRCCS, Immunol and Mol Oncol Unit, Padua, Italy .
    Casella, Cinzia
    Ist Oncol Veneto IRCCS, Immunol and Mol Oncol Unit, Padua, Italy .
    N Imyanitov, Evgeny
    NN Petrov Institute Oncol, St Petersburg, Russia .
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin, Hematol Oncol and Transfus Med Centre, Vilnius, Lithuania .
    Blanco, Ignacio
    Catalan Institute Oncol, Hereditary Canc Program, Barcelona, Spain .
    Lazaro, Conxi
    Catalan Institute Oncol, Hereditary Canc Program, Barcelona, Spain .
    B Moysich, Kirsten
    Roswell Pk Canc Institute, Department Canc Prevent and Control, Buffalo, NY 14263 USA .
    Y Karlan, Beth
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA USA .
    Gross, Jenny
    University Calif San Francisco, Department Biostat, San Francisco, CA 94143 USA University Calif San Francisco, Department Epidemiol, San Francisco, CA 94143 USA University Calif San Francisco, Department Med, San Francisco, CA 94143 USA University Calif San Francisco, Canc Risk Program, San Francisco, CA 94143 USA .
    Schmutzler, Rita
    University Hospital Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany University Hospital Cologne, Centre Integrated Oncol, Cologne, Germany .
    Wappenschmidt, Barbara
    University Hospital Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany University Hospital Cologne, Centre Integrated Oncol, Cologne, Germany .
    Meindl, Alfons
    University Munich, Department Obstet and Gynaecol, D-80539 Munich, Germany .
    Fiebig, Britta
    University Regensburg, Institute Human Genet, Regensburg, Germany .
    Sutter, Christian
    University Heidelberg, Department Human Genet, Institute Human Genet, Mol Genet Lab, Heidelberg, Germany .
    Arnold, Norbert
    University Kiel, University Hospital Schleswig Holstein, Department Obstet and Gynaecol, D-24098 Kiel, Germany .
    Deissler, Helmut
    University Hospital Ulm, Department Obstet and Gynaecol, Ulm, Germany .
    Varon-Mateeva, Raymonda
    Charite, Campus Virchov Klinikum, Institute Human Genet, Berlin, Germany .
    Kast, Karin
    Tech University Dresden, University Hospital Carl Gustav Carus, Department Obstet and Gynaecol, Dresden, Germany .
    Niederacher, Dieter
    University Dusseldorf, University Hospital Dusseldorf, Department Obstet and Gynaecol, D-4000 Dusseldorf, Germany .
    Gadzicki, Dorothea
    Hannover Med Sch, Institute Cell and Mol Pathol, D-3000 Hannover, Germany .
    Caldes, Trinidad
    Hospital San Carlos, Mol Oncol Lab, Madrid, Spain .
    Nevanlinna, Heli
    University Helsinki, Cent Hospital, Department Obstet and Gynecol, FIN-00290 Helsinki, Finland .
    Aittomaeki, Kristiina
    University Helsinki, Cent Hospital, Department Clin Genet, FIN-00290 Helsinki, Finland .
    Simard, Jacques
    Centre Hospital University Quebec, Canc Genom Lab, Quebec City, PQ Canada University Laval, Quebec City, PQ Canada .
    Soucy, Penny
    Centre Hospital University Quebec, Canc Genom Lab, Quebec City, PQ Canada University Laval, Quebec City, PQ Canada .
    B Spurdle, Amanda
    Queensland Institute Med Research, Brisbane, Qld 4006 Australia .
    Holland, Helene
    Queensland Institute Med Research, Brisbane, Qld 4006 Australia .
    Chenevix-Trench, Georgia
    Queensland Institute Med Research, Brisbane, Qld 4006 Australia .
    F Easton, Douglas
    University Cambridge, Canc Research United Kingdom Genet Epidemiol Unit, Strangeways Research Lab, Cambridge, England .
    C Antoniou, Antonis
    University Cambridge, Department Publ Hlth and Primary Care, Centre Canc Genet Epidemiol, Cambridge, England .
    Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers2011In: JOURNAL OF THE NATIONAL CANCER INSTITUTE, ISSN 0027-8874, Vol. 103, no 2Article in journal (Refereed)
    Abstract [en]

    Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. Methods We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 x 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 x 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

  • 27.
    Stenmark-Askmalm, Askmalm Marie
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    p53 Alterations in Breast Cancer Related to Prognosis and Results of Therapy1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is the most common malignant tumour disease and also the main cause of cancer-related deaths among women. The lifetime risk in western countries is 10%. The basic treatment for a patient with a localised tumour is surgery. In addition, different pathobiological variables are considered and an estimation of the risk of recurrence is made before deciding whether adjuvant therapy should be recommended. This therapy can be chemotherapy, which mainly prevents distant recurrence, or radiotherapy, which is effective against local recurrence. The treatment can be combined with anti-oestrogen, which prevents distant recurrence among patients exhibiting an oestrogen-receptor-positive tumour. However, breast cancer remains the chief cause of cancerrelated deaths and there is a need· for further pathobiologica! variables that, at an early stage, both can be prognostic and predict the outcome of adjuvant therapy.

    The p53 gene and its product p53 have been shown to play a central role in tumour suppression by regulating the cell cycle or initiating apoptosis. Certain mutations are associated with a stabilisation of the protein, leading to an accumulation that is detectable by immunohistochemistry.

    The main purposes of this study were to analyse p53 protein accumulation and gene mutation in exons 5-8 and to investigate the prognostic and predictive role of p53.

    p53 protein accumulation was investigated with immunohistochemistry in frozen tumour samples from 776 patients; 164 patients with stage U, 205 patients with stage I and 407 patients with either lymph node metastases and/or a tumour diameter exceeding 30mm. Of the latter, 139 were premenopausal and 268 were postmenopausal. These 407 patients had been randomiscd to adjuvant CMF chemotherapy or postoperative radiotherapy. Gene analyses with PCR-SSCP followed by direct sequencing were performed in the 268 postmenopausal patients. The predictive value of p53 was only analysed in the randomised patient material.

    The results showed that nuclear p53 accumulation ranged between 9% and 25%. p53 accumulation was significantly associated with several pathobiological variables, "indicating an aggressive tumour, which was more likely to be oestrogen receptor negative, DNA aneuploid, and have a high S-phase fraction. p53 accumulation was also significantly correlated with an increased rate of distant recurrence, whereas mutations that were found in 16% of the 268 cases investigated were not significantly correlated with an increased risk of distant recurrence. However, the investigation of both protein accumulation and gene mutation in exons 5-8 contributed further information than was achieved with one of the methods alone. The protein accumulation reflected to a certain extent mutations of the gene, mainly missense mutations. A majority of the severe mutations that included alteration of the reading frame did not lead to any protein accumulation. Sixty-one per cent of the tumours exhibiting protein accumulation did not show any mutation in exons 5-8. Subgroups of different p53 alteration patterns seemed to be related to different prognoses.

    The patients with p53 altered tumours, either showing protein accumulation, gene mutation or both, benefited significantly from CMF chemotherapy compared with the radiotherapy group. This benefit could not be seen among the patients without p53 alterations. The test for interaction between p53 status and relative rate was significant. This response was most pronounced among premenopausal patients. Postmenopausal patients seemed to benefit although not significantly.

    In conclusion, the present study suggests that p53 accumulation is a prognostic factor associated with an increased risk of distant recurrence. p53 alteration defined as protein accumulation, gene mutation in exons 5-8, or both, was a predictor of good response to CMF chemotherapy as compared to postoperative radiotherapy. This benefit could not be seen among patients without p53-altered tumours.

  • 28.
    Stenmark-Askmalm, Askmalm Marie
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Gentile, Massimiliano
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Arnesson, Lars-Gunnar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Protein accumulation and gene mutation of p53 in bilateral breast cancer2001In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 40, no 1, p. 56-62Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the frequency of p53 alterations in bilateral breast cancer and to evaluate a possible clonal relationship between the paired tumours regarding p53 alteration and other pathobiological variables. Tumours from 34 patients were investigated with immunohistochemistry, single strand conformation polymorphism analysis and DNA-sequence analysis applied to exons 5-8. Fifteen percent of the 68 tumours showed positive immunoreaction and/or presence of mutation. The occurrence of p53 accumulation was 9% and the prevalence of gene mutation 10%. No significant concordance was found between the tumours in the same patient for p53 alterations, progesterone receptor status or DNA ploidy. S-phase fraction showed a weak correlation, not statistically significant. Oestrogen receptor status was the only variable that exhibited a significant concordance. No convincing evidence was found for other associations between the paired tumours or for a high prevalence of p53 alterations in bilateral breast cancer.

  • 29.
    Söderlund, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Queseth, Siv
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Karolinska University Hospital.
    Marie Stenmark, Askmalm
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer2010In: INTERNATIONAL JOURNAL OF ONCOLOGY, ISSN 1019-6439, Vol. 37, no 6, p. 1547-1554Article in journal (Refereed)
    Abstract [en]

    The purpose was to study the prognostic and predictive roles of DNA protein kinase catalytic subunit (DNA-PKcs), Ku70/80 and p53 for the effect of radiotherapy in breast cancer patients Protein expressions of Ku70/80, DNA-PKcs and p53 were examined using immunohistochemistry in tumours from 224 breast cancer patients, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil) One hundred and twenty-nine (60%) of the tumours had low expression of Ku70180, 122 (57%) had low expression of DNA-PKcs and 65 (30%) had altered p53 expression None of the proteins were indicative to the prognosis of local recurrence-free survival Even though the expression of Ku70/80 and DNA-PKcs correlated well, they were not associated with treatment outcome in the same way Low expression of Ku70/80 predicted good effect of radiotherapy (RR=0 31, 95% CI 0 13-0 76, p=0 01) In contrast, the greatest benefit of radiotherapy over chemotherapy was seen in patients with high DNA-PKcs expression (RR=0 25, 95% CI 0 07-0 84, p=0 02) Altered p53 expression predicted poor response to radiotherapy We believe that the results reflect the different roles of DNA-PKcs and Ku70/80 in repair and cell death regulation after DNA damage These differences could be of importance when developing drugs that target DNA repair

  • 30.
    Söderlund, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Fornander, Tommy
    Departmen of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer2007In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 84, no 3, p. 242-251Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: The breast cancer susceptibility genes BRCA1 and BRCA2 interact with Rad51, one of the central components in the homologous recombination repair pathway. This study evaluates the prognostic and predictive role of BRCA1, BRCA2 and Rad51, individually and as a complex, in breast cancer.

    Material and Methods: Expression of BRCA1, BRCA2 and Rad51 was investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive postoperative radiotherapy or adjuvant chemotherapy (CMF).

    Results: 53% (112/212) of the tumours had reduced expression of the BRCA1/BRCA2/Rad51 complex. Low expression correlated to high histologic grade (p=0.05). Patients with low expression of the complex developed significantly more local recurrences as compared to patients with high expression (RR=3.20, 95% C.I. 1.48-6.88, p=0.003). Expression of the BRCA1/BRCA2/Rad51 complex was an independent prognostic factor in multivariate analysis (p=0.03). Patients with low expression of the complex responded well to radiotherapy (RR=0.31, 95% C.I. 0.14-0.70, p=0.005), whereas patients with high expression had few local recurrences and no additional benefit from radiotherapy (RR=1.08, 95% C.I. 0.40-2.90, p=0.88).

    Conclusions: Low expression of the BRCA1/BRCA2/Rad51 complex is a marker of poor prognosis, but predicts good effect of radiotherapy in patients with early breast cancer.

  • 31.
    Söderlund Leifler, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    ¨, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Rutqvist, Lars Erik
    Department of Medicine/Huddinge, Karolinska Institute, Stockholm,Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer2007In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 68, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    Purpose: Post-operative radiotherapy is offered to a majority of breast cancer patients, since it significantly reduces the risk of local recurrence. However, some patients still develop recurrences. Owing to their vital roles in the repair of radiation-induced double-strand breaks, the Mre11/Rad50/Nbs1 (MRN) complex and the ATM protein might be implicated in tumour cell resistance to radiotherapy. The aim of this study was to investigate the expression and predictive role of these DNA repair proteins for the outcome of radiotherapy in breast cancer patients.

    Patients and Methods: The protein expression of ATM and the proteins in the MRN complex were investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (CMF).

    Results: Compared to normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1 and ATM was reduced in a majority of the tumours. Weak expression of the MRN complex was correlated to high histological grade and ER negativity (p=0.01 and p=0.0001). Radiotherapy significantly reduced the risk of local recurrence as compared to chemotherapy (p=0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (RR=0.27, 95% C.I. 0.098-0.72, p=0.009), whereas patients with negative/weak MRN had no benefit of radiotherapy compared to CMF. These results suggest that an intact MRN complex is important for the tumour cell eradicating effect of radiotherapy.

  • 32.
    Söderlund Leifler, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Asklid, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Fornander, Tommy
    Department of Oncology, karolinska Unvíversity Hospital, Stockholm, Sweden.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    The RAD51 135G/C polymorphism is related to the effect of adjuvant therapy in early breast cancer2015In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 141, no 5, p. 797-804Article in journal (Refereed)
    Abstract [en]

    Purpose: A single-nucleotide polymorphism, RAD51 135G/C, in the untranslated region of the RAD51 gene has been found to elevate breast cancer risk among BRCA2 carriers. The purpose of this study was to investigate if this polymorphism is related to RAD51 protein expression, prognosis of early breast cancer and if it contributes to resistance to radiotherapy or cyclophosphamide/5-fluorouracil/methotrexate (CMF) chemotherapy.

    Methods: We genotyped 306 patients with early breast cancer, who were randomised to receive post-operative radiotherapy or CMF chemotherapy, for the RAD51 135G/C polymorphism. Expression of RAD51 protein was evaluated with immunohistochemistry.

    Results: The frequency of C-allele was 15.4% (including three C/C homozygotes). There was no correlation between genotype and protein expression pattern in tumours. Patients who were homozygous for the wildtype G/G genotype had a significant benefit of radiotherapy (RR=0.32, 95% C.I. 0.16-0.64, p=0.001). CMF chemotherapy significantly reduced the risk of distant recurrence during the first 20 years in patients who had the C-allele (RR=0.29, 95% C.I. 0.10-0.88, p=0.03), whereas patients who were G/G homozygotes had no benefit from chemotherapy over radiotherapy (RR=1.09, 95% C.I. 0.77-1.6, p=0.61). There was a significant interaction between chemotherapy and genotype (p=0.02). Genotype was not related to the rate of distant recurrence among patients treated with radiotherapy.

    Conclusion: Breast cancer patients who were homozygous for the wildtype G allele had a significant benefit of radiotherapy. The results suggest that the RAD51 135G/C polymorphism predicts the effect of CMF chemotherapy in early breast cancer.

  • 33.
    Tzortzatos, Gerasimos
    et al.
    Karolinska Institute, Sweden.
    Andersson, Emil
    Karolinska Institute, Sweden.
    Soller, Maria
    Skåne University Hospital, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Medicine and Health Sciences.
    Zagoras, Theofanis
    University of Gothenburg, Sweden.
    Georgii-Hemming, Patrik
    Uppsala University, Sweden.
    Lindblom, Annika
    Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Tham, Emma
    Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Mints, Miriam
    Karolinska Institute, Sweden.
    The gynecological surveillance of women with Lynch Syndrome in Sweden2015In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 138, no 3, p. 717-722Article in journal (Refereed)
    Abstract [en]

    Objective. Women with Lynch syndrome (LS) have up to a 60% lifetime risk of endometrial cancer (EC) and up to a 24% risk of ovarian cancer (OC). Gynecological surveillance is recommended, but the benefit and how it should be performed remain unclear. The purpose of this study was to assess diagnostic modalities for gynecological screening of LS patients in Sweden and clinical outcome. Methods. A retrospective nationwide study of 170 women with molecularly confirmed LS. Data including gynecological LS screening history, biopsy results (if any), genetic records, number of screening visits, results from screening including transvaginal ultrasound (TVUS), endometrial biopsy (EB), blood test for tumor marker cancer antigen (CA) 125, prophylactic surgery including age at procedure, and setting from which screening data were obtained from medical records. Results. A total of 117 women were eligible for gynecological screening and of these, 86 patients attended screening visits. Of these, 41 underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy. Two patients (4.9%) were diagnosed with EC and two (4.9%) with precancerous lesions in conjunction with prophylactic surgery. Total incidence of gynecological cancer in the surveillance group (45 women) was 20% EC, 4% OC. Five patients had endometrial cancer or complex hyperplasia with atypia (n = 2) detected by endometrial biopsy. Four additional cases were detected due to interval bleeding. Both cases of ovarian cancer were detected by transvaginal ultrasound in patients with ovarian cysts under surveillance. The youngest woman with endometrial cancer was diagnosed at 35 years of age, before she was aware of her diagnosis of Lynch syndrome. Conclusions. Gynecological surveillance of women with Lynch syndrome may lead to earlier detection of precancerous lesions, which might have some impact on the morbidity from endometrial cancer although further studies are needed to prove this. Prophylactic hysterectomy with or without bilateral salpingo-oophorectomy reduces the cancer incidence. A practical approach to surveillance in Lynch syndrome women would be to offer annual surveillance beginning at age 30 years including probably both TVUS and EB in order to increase diagnostic yield with prospective data registry for follow-up studies. Prophylactic surgery could be performed at a suitable age after childbearing to obtain a balance between reducing the risk of cancer and minimizing long-term complications from premature menopause. (C) 2015 Elsevier Inc. All rights reserved.

  • 34.
    van Thuijl, Hinke F.
    et al.
    University of Calif San Francisco, CA 94143 USA; Vrije University of Amsterdam Medical Centre, Netherlands; Vrije University of Amsterdam Medical Centre, Netherlands.
    Mazor, Tali
    University of Calif San Francisco, CA 94143 USA.
    Johnson, Brett E.
    University of Calif San Francisco, CA 94143 USA.
    Fouse, Shaun D.
    University of Calif San Francisco, CA 94143 USA.
    Aihara, Koki
    University of Tokyo, Japan; University of Tokyo, Japan.
    Hong, Chibo
    University of Calif San Francisco, CA 94143 USA.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Heimans, Jan J.
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Kloezeman, Jenneke J.
    Erasmus MC, Netherlands.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lamfers, Martine L. M.
    Erasmus MC, Netherlands.
    Saito, Nobuhito
    University of Tokyo, Japan.
    Aburatani, Hiroyuki
    University of Tokyo, Japan.
    Mukasa, Akitake
    University of Tokyo, Japan.
    Berger, Mitchell S.
    University of Calif San Francisco, CA 94143 USA.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Taylor, Barry S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Molinaro, Annette M.
    University of Calif San Francisco, CA 94143 USA; University of Calif San Francisco, CA 94143 USA.
    Wesseling, Pieter
    Vrije University of Amsterdam Medical Centre, Netherlands; Radboud University of Nijmegen, Netherlands.
    Reijneveld, Jaap C.
    Vrije University of Amsterdam Medical Centre, Netherlands; University of Amsterdam, Netherlands.
    Chang, Susan M.
    University of Calif San Francisco, CA 94143 USA.
    Ylstra, Bauke
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Costello, Joseph F.
    University of Calif San Francisco, CA 94143 USA.
    Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment2015In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, no 4, p. 597-607Article in journal (Refereed)
    Abstract [en]

    Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-na less than ve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

  • 35.
    von Salome, Jenny
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Boonstra, Philip S.
    University of Michigan, MI 48109 USA.
    Karimi, Masoud
    Karolinska University Hospital, Sweden.
    Silander, Gustav
    Umeå University, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Gebre-Medhin, Samuel
    Off Medical Serv, Sweden; Lund University, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Nilbert, Mef
    Lund University, Sweden; University of Copenhagen, Denmark.
    Lindblom, Annika
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Lagerstedt-Robinson, Kristina
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Genetic anticipation in Swedish Lynch syndrome families2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 10, article id e1007012Article in journal (Refereed)
    Abstract [en]

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linkoping, Uppsala and Umea between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.

  • 36.
    Wegman (Palmebäck), Pia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Rutqvist, Lars-Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Wingren, Sten
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients2006In: Pharmacogenetics and Genomics, ISSN 1744-6872, Vol. 16, no 5, p. 347-351Article in journal (Refereed)
    Abstract [en]

    Background: Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress.

     

    Methods: In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen.

     

    Results: Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12–0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088).

     

    Conclusion: The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.

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