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  • 201.
    Miller, T W
    et al.
    Vanderbilt University.
    Perez-Torres, M
    Vanderbilt University.
    Wu, H
    Vanderbilt University.
    Shyr, Y
    Vanderbilt University.
    Guix, M
    Vanderbilt University.
    Jiang, A
    Vanderbilt University.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Arteaga, C L
    Vanderbilt University.
    Loss of PTEN engages ErbB3 and IGF-I receptor signaling to promote antiestrogen resistance in breast cancer.2009Inngår i: CANCER RESEARCH ISSN 0008-5472: Volume 69 Issue 2, 2009, Vol. 69, nr 2, s. 80S-81SKonferansepaper (Fagfellevurdert)
  • 202.
    Miller, Todd W
    et al.
    Vanderbilt University.
    Narasanna, Archana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gonzalez-Angulo, Ana M
    University of Texas.
    Hennessy, Bryan T
    University of Texas.
    Mills, Gordon B
    University of Texas.
    Kennedy, J Phillip
    Vanderbilt University.
    Lindsley, Craig W
    Vanderbilt University.
    Arteaga, Carlos L
    Vanderbilt University.
    Loss of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Engages ErbB3 and Insulin-Like Growth Factor-I Receptor Signaling to Promote Antiestrogen Resistance in Breast Cancer2009Inngår i: CANCER RESEARCH, ISSN 0008-5472, Vol. 69, nr 10, s. 4192-4201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Knockdown of the tumor suppressor phosphatase Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) with shRNA in three estrogen receptor (ER)-positive breast cancer cell lines resulted in increased phosphatidylinositol-3 kinase (PI3K) and AKT activities, resistance to tamoxifen and fulvestrant, and hormone-independent growth. PTEN knockdown induced the up-regulation of ER transcriptional activity in MCF-7 cells but decreased ER protein levels and transcriptional activity in T47D and MDA-361 cells. Tamoxifen and fulvestrant treatment inhibited estradiol-induced Ell transcriptional activity in all shPTEN cell lines but did not abrogate the increased cell proliferation induced by PTEN knockdown. PTEN knockdown increased basal and ligand-induced activation of the insulin-like growth factor-I (IGF-I) and ErbB3 receptor tyrosine kinases, and prolonged the association of the p85 PI3K subunit with the IGF-I receptor (IGF-IR) effector insulin receptor substrate-1 and with ErbB3, implicating VITA in the modulation of Signaling upstream of PI3K. Consistent with these data, PTEN levels inversely correlated with levels of tyrosine-phosphorylated IGF-IR in tissue lysate arrays of primary breast cancers. Inhibition of IGF-IR and/or ErbB2-mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone dependence and the growth inhibitory effect of tamoxifen and fulvestrant. oil shPTEN cells, suggesting that cotargeting both Ell and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+, PTEN-deficient breast cancers.

  • 203.
    Mohty, M.
    et al.
    Service d'Hématologie Clinique, CHU Hôtel Dieu, Université de Nantes, Nantes, France, Service d'Hématologie Clinique, CHU Hôtel-Dieu, Université de Nantes, Place Alexis Ricordeau, F-44093 Nantes, France.
    Labopin, M.
    European Group for Blood and Marrow Transplantation (EBMT), Hopital Saint-Antoine, Université de Paris 6, Pierre et Marie Curie, Paris, France.
    Tabrizzi, R.
    Centre Hospitalo-Universitaire de Bordeaux, Hôpital Haut-Leveque, Pessac, France.
    Theorin, Niklas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Fauser, A.A.
    Klinik fuer Knochenmarktransplantation und Haematologie/Onkologie, Idar-Oberstein, Germany.
    Rambaldi, A.
    Ospedale Bergamo, Divisione di Ematologia, Bergamo, Italy.
    Maertens, J.
    University Hospital Gasthuisberg, Dept. of Hematology, Leuven, Belgium.
    Slavin, S.
    Hadassah University Hospital, Department of Bone Marrow Transplantation, Jerusalem, Israel.
    Majolino, I.
    Ospedale S. Camillo-Forlanini, Dept. of Hematology and BMT, Rome, Italy.
    Nagler, A.
    Tel-Aviv University, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
    Blaise, D.
    Unité de Transplantation et de Thérapie Cellulaire, Institut Paoli-Calmettes, Marseille, France.
    Rocha, V.
    European Group for Blood and Marrow Transplantation (EBMT), Hopital Saint-Antoine, Université de Paris 6, Pierre et Marie Curie, Paris, France, Department of Hematology, Hopital Saint-Louis, Assistance Publique Hopitaux de Paris, Paris, France.
    Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: A retrospective study from the European Group for Blood and Marrow Transplantation2008Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 93, nr 2, s. 303-306Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This retrospective study reported the outcome of 97 adult acute lymphoblastic leukemia patients who received a reduced-intensity conditioning allogeneic stem cell transplantation. With a median follow-up of 2.8 years, two year overall-survival, leukemia-free survival and non-relapse mortality were significantly better in patients transplanted in first complete remission (CR1, 52±9%, 42±10%, and 18±7% respectively) compared with those transplanted in more advanced phase (p=0.003, p=0.002 and p=0.01 respectively). In multivariate analysis, disease status (CR1 vs. advanced, p=0.001) and chronic graft-vs-host disease (p=0.01) were associated with an improved overall-survival, suggesting that reduced-intensity conditioning allogeneic stem cell transplantation is feasible in patients with high risk lymphoblastic leukemia in remission at transplantation. ©2008 Ferrata Storti Foundation.

  • 204.
    Mohty, Mohamad
    et al.
    CHU Nantes.
    Labopin, Myriam
    Hop St Antoine.
    Basara, Nadezda
    University of Leipzig.
    Cornelissen, Jan J
    Erasmus MC Daniel Den Hoed, Rotterdam, Netherlands .
    Tabrizi, Reza
    CHU Bordeaux.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Perez Simon, Jose Antonio
    Hospital University Salamanca.
    Nagler, Arnon
    Chaim Sheba Medical Centre.
    Kroger, Nicolaus
    University of Hamburg Hospital.
    Rio, Bernard
    Hop Hotel Dieu.
    Martino, Rodrigo
    Hospital Santa Creu and Sant Pau.
    Eder, Matthias
    Hannover Medical School.
    Bilger, Karin
    Hop Hautepierre, Strasbourg, France .
    W Bunjes, Donald W
    University of Ulm Klinikum.
    Socie, Gerard
    Institute J Paoli I Calmettes.
    Polge, Emmanuelle
    EBMT Paris Off.
    Rocha, Vanderson
    Hop St Louis.
    Association Between the Hematopoietic Cell Transplantation-Specific Comorbidity Index (CI) and Non-Relapse Mortality (NRM) After Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) in First Complete Remission (CR1) in BLOOD, vol 114, issue 22, pp 270-2702009Inngår i: BLOOD, American Society of Hematology , 2009, Vol. 114, nr 22, s. 270-270Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 205.
    Mohty, Mohamad
    et al.
    CHU Nantes.
    Labopin, Myriam
    EBMT Paris.
    Milpied, Noel-Jean
    Erasmus MC Daniel Den Hoed.
    Blaise, Didier
    Institute J Paoli I Calmettes.
    Petersen, Eefke
    University Medical Centre Utrecht.
    Theorin, Niklas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Goker, Hakan
    Hacettepe University.
    Socie, Gerard
    Hop St Louis.
    Impact of Cytogenetics Risk on Outcome after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) from An HLA Identical Sibling for Patients with Acute Myeloid Leukemia (AML) in First Complete Remission (CR1)2008Inngår i: American Society of Hematology Meeting: in: Blood Volume 112, Issue 11, 2008, Vol. 112, nr 11, s. 134-135Konferansepaper (Fagfellevurdert)
  • 206.
    Moparthi, Satish Babu
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Bergman, Viveka
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Adell, Gunnar
    Karolinska University Hospital.
    Thorstensson, Sten
    Kalmar Hospital.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    pRb2/p130 protein in relation to clinicopathological and biological variables in rectal cancers with a clinical trial of preoperative radiotherapy2009Inngår i: INTERNATIONAL JOURNAL OF COLORECTAL DISEASE, ISSN 0179-1958, Vol. 24, nr 11, s. 1303-1310Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    pRb2/p130 plays a key role in cell proliferation and is a considerable progress about expression patterns of pRb2/p130 in number of malignancies. However, pRb2/p130 expression and its significance in rectal cancer remain unknown. The purpose of the present study was to investigate pRb2/p130 protein patterns and their correlations with clinicopathological and biological factors in rectal cancer patients with or without preoperative radiotherapy (RT). pRb2/p130 protein was examined by immunohistochemistry in 130 primary tumors, along with the corresponding 61 distant normal mucosa specimens, 85 adjacent normal mucosa specimens, 34 lymph node metastases, and 93 primary tumor biopsies from rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. The pRb2/p130 protein was mainly localized in the cytoplasm of tumor cells. In nonradiated cases, the lack of pRb2/p130 was related to advanced tumor-node-metastases stage, poorer differentiation, weak fibrosis, less inflammatory infiltration, higher Ki-67, and positive Cox-2 expression (p andlt; 0.05). In radiated cases, the lack of pRb2/p130 was related to nonstaining of Cox-2 and survivin (p andlt; 0.05). pRb2/p130 protein in primary tumors tended to be increased after RT (27% vs 16%, p = 0.07). pRb2/p130 was mainly localized in the cytoplasm rather than in the nucleus in rectal cancer. After RT, pRb2/p130 protein seems to be increased in primary tumors, and further the relationship of the pRb2/p130 with the clinicopathological and biological variables changed compared to the nonradiated cases. However, we did not find that the pRb2/p130 was directly related to RT, tumor recurrence, and patients survival.

  • 207.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    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 BRCA1/22011Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, nr 6Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 208.
    Mustjoki, Satu
    et al.
    University of Helsinki.
    Richter, Johan
    Lund University Hospital.
    Barbany, Gisela
    Karolinska University Hospital.
    Dybedal, Ingunn
    University of Oslo.
    Fioretos, Thoas
    Lund University Hospital.
    Gedde Dahl, Tobias
    University of Oslo.
    Gjertsen, Bjorn T
    Haukeland Hospital.
    Hovland, Randi
    Haukeland Hospital.
    Jalkanen, Sari
    University of Helsinki.
    Josefsen, Dag
    Norwegian Radium Hospital.
    Koskenvesa, Perttu
    University Helsinki.
    Lassen, Carin
    Lund University Hospital.
    Latvala, Kirsi
    University of Helsinki.
    Majeed, Waleed
    Stavanger University Hospital.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Markevarn, Berit
    Norrland University Hospital.
    Moshfegh, Ali
    Karolinska University Hospital.
    Ohm, Lotta
    Karolinska University Hospital.
    Olofsson, Tor
    Lund University Hospital.
    Olsson Stromberg, Ulla
    University Uppsala Hospital.
    Rapakko, Katrin
    Oulu University Hospital.
    Remes, Kari
    Turku University.
    Stentoft, Jesper
    Arhus University Hospital.
    Stenke, Leif
    Karolinska University Hospital.
    Suominen, Merja
    Kanta Hame Cent Hospital.
    Thunberg, Sara
    Karolinska University Hospital.
    Weiss Bjerrum, Ole
    Rigshosp, Copenhagen.
    Simonsson, Bengt
    University Uppsala Hospital.
    Porkka, Kimmo
    University Helsinki.
    Hjorth Hansen, Henrik
    St Olavs Hospital.
    The Proportion of Ph+CD34(+)CD38(neg) Leukemic Stem Cells In the Bone Marrow of Newly Diagnosed Patients with Chronic Myeloid Leukemia (CML) In Chronic Phase (CP) Is Variable and Correlates with High Sokal Risk, High Leukocyte Count, Low Hemoglobin Concentration, Splenomegaly and Increased Hematological Toxicity During Initial TKI Therapy Data From a Randomized Phase II NordCML006 Study2010Inngår i: BLOOD vol 116, issue 21 (ISSN 0006-4971), American Society of Hematology , 2010, Vol. 116, nr 21, s. 291-292Konferansepaper (Fagfellevurdert)
  • 209.
    Mustjoki, Satu
    et al.
    HUCH.
    Richter, Johan
    Skåne University Hospital.
    Barbany, Gisela
    Karolinska University Hospital.
    Ehrencrona, Hans
    Skåne University Hospital.
    Dybedal, Ingunn
    University of Oslo.
    Fioretos, Thoas
    Lund University.
    Gedde-Dahl, Tobias
    University Hospital, Oslo.
    Gjertsen, Bjorn
    Haukeland Hospital.
    Hovland, Randi
    Haukeland Hospital.
    E Jalkanen, Sari
    HUCH.
    Josefsen, Dag
    Norwegian Radium Hospital.
    Koskenvesa, Perttu
    HUCH.
    Lassen, Carin
    Skåne University Hospital.
    Latvala, Kirsi
    HUCH.
    Majeed, Waleed
    Stavanger University Hospital.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Markevarn, Berit
    Umeå University Hospital.
    Mosfegh, Ali
    Karolinska University Hospital.
    Ohm, Lotta
    Karolinska University Hospital.
    Olofsson, Tor
    Skåne University Hospital.
    Olsson-Stromberg, Ulla
    University of Uppsala Hospital.
    Rapakko, Katrin
    Oulu University Hospital.
    Remes, Karil
    Turku University.
    Stentoft, Jesper
    Aarhus University Hospital.
    Stenke, Leif
    Karolinska University Hospital.
    Suominen, Merja
    Kanta Hame Central Hospital.
    Thunberg, Sara
    Karolinska University Hospital.
    Weiss Bjerrum, Ole
    University of Copenhagen Hospital.
    Simonsson, Bengt
    University of Uppsala Hospital.
    Porkka, Kimmo
    HUCH.
    Hjorth-Hansen, Henrik
    St Olavs University Hospital.
    Favorable Therapeutic Responses in Newly Diagnosed CML-CP Patients Induced by Dasatinib Are Reflected At the CD34+CD38+Progenitor Cell but Not At the CD34+CD38-Stem Cell Level: Results From Randomized NordCML006 Study in BLOOD, vol 118, issue 21, pp 356-3562011Inngår i: BLOOD, American Society of Hematology , 2011, Vol. 118, nr 21, s. 356-356Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 210.
    Nagler, A
    et al.
    Chaim Sheba Medical Centre.
    Labopin, M
    University of Paris 06.
    Shimoni, A
    Chaim Sheba Medical Centre.
    Mufti, G
    GKT School of Medicine.
    Cornelissen, J J
    Erasmus MC, Netherlands .
    Blaise, D
    Institute J Paoli I Calmettes.
    Janssen, J J W M
    Vrije University Amsterdam.
    Milpied, N
    CHU Bordeaux.
    Vindelov, L
    Rigshospital, Copenhagen.
    Petersen, E
    University Medical Centre, Utrecht.
    Gribben, J
    St Bartholomews and Royal London Hospital.
    Bacigalupo, A
    Osped San Martino Genova.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Niederwieser, D
    University Hospital Leipzig.
    Socie, G
    Hopital St Louis, Paris.
    Arnold, R
    Charite, Campus Virchow Klinikum.
    Brown, P
    St James Hospital.
    Goker, H
    Hacettepe University.
    Mohty, M
    Hematol Clinic, Nantes.
    Rocha, V
    Department Hematology, Paris.
    Mobilized peripheral blood stem cells compared with bone marrow for related reduced-intensity transplantation in acute myeloid leukaemia in complete remission: a retrospective analysis from the ALWP of EBMT in BONE MARROW TRANSPLANTATION, vol 45, issue , pp S21-S222010Inngår i: BONE MARROW TRANSPLANTATION, Nature Publishing Group , 2010, Vol. 45, s. S21-S22Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 211.
    Nagler, Arnon
    et al.
    Chaim Sheba Medical Centre, Israel .
    Labopin, Myriam
    UPMC University of Paris, France .
    Shimoni, Avichai
    Chaim Sheba Medical Centre, Israel .
    Mufti, Ghulam J
    Kings Coll London, England .
    Cornelissen, Jan J
    Erasmus Medical Centre Daniel den Hoed, Netherlands .
    Blaise, Didier
    Institute J Paoli I Calmettes, France .
    Janssen, Jeroen J W M
    Vrije University of Amsterdam, Netherlands .
    Milpied, Noel
    CHU Bordeaux, France .
    Vindelov, Lars
    Rigshosp, Denmark .
    Petersen, Eefke
    University of Medical Centre, Netherlands .
    Gribben, John
    St Bartholomews and Royal London Hospital, England .
    Bacigalupo, Andrea
    Osped San Martino Genova, Italy .
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Niederwieser, Dietger
    University Hospital Leipzig, Germany .
    Socie, Gerard J
    Hop St Louis, France .
    Arnold, Renate
    Charite, Germany .
    Brown, Paul
    St James Hospital, Ireland .
    Goker, Hakan
    Hacettepe University, Turkey .
    Rocha, Vanderson
    CHU Nantes, France .
    Mohty, Mohamad
    EBMT ALWP, France University of Paris 07, France .
    Mobilized peripheral blood stem cells compared with bone marrow from HLA-identical siblings for reduced-intensity conditioning transplantation in acute myeloid leukemia in complete remission: a retrospective analysis from the Acute Leukemia Working Party of EBMT2012Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 89, nr 3, s. 206-213Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Reduced-intensity conditioning (RIC)-alloSCT is increasingly used for acute myelogenous leukemia. Limited data are available for the comparison of peripheral blood stem cells with bone marrow for RIC-alloSCT. We used the European Group for Blood and Marrow Transplantation (EBMT) ALWP data to compare the outcome of mobilized peripheral blood stem cells (PBSC) (n = 1430) vs. bone marrow (BM) (n = 107) for acute myelogenous leukemia (AML) patients with complete remission that underwent RIC-alloSCT from compatible sibling donors. The leukemia features, the disease status, and the time from diagnosis were similar between the two groups. Engraftment was achieved in 99% and 93% in the PBSC and BM groups, respectively (P andlt; 0.0001). The day of engraftment was significantly earlier for the PBSC vs. the BM group, 15 (159) and 19 (569), respectively (P andlt; 0.001). Acute GVHD, severe GVHD (grade IIIIV) and chronic GVHD did not differ between the groups. leukemia-free survival (LFS), relapse, and non-relapsed mortality (NRM) were 51 +/- 2%, 32 +/- 1%, and 17 +/- 1% vs. 50 +/- 6%, 38 +/- 6%, and 12 +/- 3% for the PBSC and BM groups, respectively. Our results indicate faster engraftment, but no difference in GVHD, LFS, relapse, and NRM when comparing PBSC to BM grafts from sibling donors following RIC conditioning. This is the first study comparing PBSC to BM grafts in the RIC setting, analyzing a homogeneous population of patients with AML in remission. Whether PBSC should be preferred for advanced phases of the disease, where the outcome is dominated by relapse incidences, needs further investigation.

  • 212.
    Nilsson, Cecilia
    et al.
    Vastmanland County Hospital, Sweden .
    Johansson, Ida
    Lund University, Sweden .
    Ahlin, Cecilia
    Örebro University Hospital, Sweden .
    Thorstenson, Sten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Amini, Rose-Marie
    Uppsala University, Sweden .
    Holmqvist, Marit
    Uppsala Örebro Regional Oncology Centre, Sweden .
    Bergkvist, Leif
    Lund University, Sweden .
    Hedenfalk, Ingrid
    Lund University, Sweden .
    Fjallskog, Marie-Louise
    Uppsala University, Sweden .
    Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact2013Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, nr 1, s. 102-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Male breast cancer (MBC) is an uncommon disease and there is limited information on the prognostic impact of routinely used clinicopathological parameters. Material and methods. In a retrospective setting, we reviewed 197 MBC patients with accessible paraffin-embedded tumor tissue and clinicopathological data. Immunohistochemical (IHC) stainings were performed on tissue microarrays and histological grading on conventional slides. Cox proportional regression models were applied for uni- and multivariate analyses using breast cancer death as the event. Results. Estrogen receptor (ER) and progesterone receptor positivity were demonstrated in 93% and 77% of patients, respectively. Nottingham histologic grade (NHG) III was seen in 41% and HER2 positivity in 11%. Classification into molecular subtypes using IHC markers according to three alternative definitions revealed luminal A and luminal B in 81% vs. 11%; 48% vs. 44% and 41% vs. 42% of cases. Two cases of basal-like were identified, but no cases of HER2-like. Factors associated with an increased risk of breast cancer death were node positivity (HR 4.5; 95% CI 1.8-11.1), tumor size andgt;20 mm (HR 3.3; 95% CI 1.4-7.9) and ER negativity (HR 10.9; 95% CI 3.2-37.9). No difference in breast cancer death between the luminal subgroups was demonstrated, regardless of definition. Conclusion. MBC tumors were more often of high grade, whereas HER2 overexpression was as frequent as in FBC. Lymph nodes, tumor size and ER status were independent predictors of breast cancer death. The prognostic impact of molecular subtyping in MBC seems to differ from that previously established in FBC.

  • 213.
    Nilsson, Cecilia
    et al.
    Vastmanland County Hospital, Sweden .
    Koliadi, Anthoula
    Uppsala University, Sweden .
    Johansson, Ida
    Lund University, Sweden .
    Ahlin, Cecilia
    Örebro University Hospital, Sweden .
    Thorstenson, Sten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Bergkvist, Leif
    Vastmanland County Hospital, Sweden .
    Hedenfalk, Ingrid
    Lund University, Sweden .
    Fjallskog, Marie-Louise
    Uppsala University, Sweden .
    High proliferation is associated with inferior Outcome in male breast cancer patients2013Inngår i: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 26, nr 1, s. 87-94Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Assessment of proliferation is important in female breast cancer and individual treatment decisions are based upon its results, especially in the lumina! subgroups. Gene expression analyses fail to group male breast cancer into the intrinsic subgroups previously established in female breast cancer. Even though proliferation has been shown to divide male breast cancer into molecular subgroups with different prognoses, the clinical importance of proliferation markers has not yet been elucidated. Previous studies in male breast cancer have demonstrated contradictory results regarding the prognostic impact of histological grade and Ki-67, parameters strongly associated with proliferation. The aim of the present project was to study proliferation in male breast cancer by assessing other proliferation-related markers viz. cyclins A, B, D1 and mitotic count. A total of 197 male breast cancer cases with accessible paraffin-embedded material and outcome data were investigated. Immunohistochemical stainings were performed on tissue microarrays. Kaplan-Meier estimates and the Cox proportional regression models were used for survival analyses with breast cancer death as the event. The subset of patients with high expression of cyclin A (hazard ratio (HR) 3.7; P=0.001) and B (HR 2.7; P=0.02) demonstrated a poorer survival. Furthermore, high mitotic count was associated with an increased risk of breast cancer death (HR 2.5; P=0.01). In contrast, cyclin D1 overexpression was predictive of better breast cancer survival (HR 0.3; P=0.001). In conclusion, high levels of cyclin A and B expression and an elevated mitotic count result in a two to threefold higher risk for breast cancer death, whereas cyclin D1 overexpression halves the risk. The clinical utility of these proliferation markers needs further elucidation. Modern Pathology (2013) 26, 87-94; doi:10.1038/modpathol.2012.145; published online 24 August 2012

  • 214.
    Nilsson, Torbjorn K.
    et al.
    Örebro University Hospital, Sweden University of Örebro, Sweden .
    Lof-Ohlin, Zarah M.
    Örebro University Hospital, Sweden .
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    DNA methylation of the p14(ARF), RASSF1A and APC1A genes as an independent prognostic factor in colorectal cancer patients2013Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 42, nr 1, s. 127-133Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We quantitated the methylated fraction of CpG sites in the promoter regions of O-6-MGMT, p14(ARF), p16(INK4a), RASSF1A and APC1A in tumor tissue from patients with colorectal cancer (CRC) in order to determine if promoter hypermethylation of any of these genes predicts survival. DNA was isolated from 111 primary CRC and 46 matched normal colorectal mucosa samples from the same patients, obtained at primary surgery and DNA methylation was examined by Pyrosequencing (R). Follow-up time was up to 20 years. Patients showed partial promoter methylation in the following frequencies: O-6-MGMT, 34%; p14(ARF), 29%; p16(INK4a), 28%; RASSF1A, 14%; and APC1A, 27%. Normal mucosa was always unmethylated. CRC patients with methylated p14(ARF). gene promoter had significantly worse prognosis (p=0.036), whereas those with methylated O-6-MGMT had significantly better prognosis through the first 60 months post-treatment (RR 0.36; p=0.023). Methylation of one or more of the genes from the set p14(ARF), RASSF1A and APC1A, was significantly (p=0.021) associated with worse prognosis even adjusting for tumor stage and differentiation (RR 2.2, p=0.037). Thus, DNA methylation of the p14(ARF), RASSF1A and APC1A genes, diagnosed by Pyrosequencing, defines a poor prognosis subset of CRC patients independently of both tumor stage and differentiation. O-6-MGMT methylation may play a protective role.

  • 215.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Angiogenin Regulation by Estradiol in Breast Tissue: Tamoxifen Inhibits Angiogenin Nuclear Translocation and Antiangiogenin Therapy Reduces Breast Cancer Growth In vivo2010Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, nr 14, s. 3659-3669Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Angiogenin, a 14.2-kDa polypeptide member of the RNase A superfamily, has potent angiogenic effects. Nuclear accumulation of angiogenin is essential for its angiogenic activity. Increased angiogenin expression has been associated with the transition of normal breast tissue into invasive breast carcinoma. In this article, we investigated whether estradiol (E-2) affected angiogenin in breast tissue. Experimental Design: We used microdialysis for sampling of extracellular angiogenin in vivo. In vitro cultures of whole normal breast tissue, breast cancer cells, and endothelial cells were used. Results: We show that extracellular angiogenin correlated significantly with E-2 in normal human breast tissue in vivo and that exposure of normal breast tissue biopsies to E-2 stimulated angiogenin secretion. In breast cancer patients, the in vivo angiogenin levels were significantly higher in tumors compared with the adjacent normal breast tissue. In estrogen receptor-positive breast cancer cells, E-2 increased and tamoxifen decreased angiogenin secretion. Moreover, E-2-induced angiogenin derived from cancer cells significantly increased endothelial cell proliferation. Tamoxifen reversed this increase as well as inhibited nuclear translocation of angiogenin. In vivo, in experimental breast cancer, tamoxifen decreased angiogenin levels and decreased angiogenesis. Additionally, treating tumor-bearing mice with an antiangiogenin antibody resulted in tumor stasis, suggesting a role for angiogenin in estrogen-dependent breast cancer growth. Conclusion: Our results suggest previously unknown mechanisms by which estrogen and antiestrogen regulate angiogenesis in normal human breast tissue and breast cancer. This may be important for estrogen-driven breast cancer progression and a molecular target for therapeutic interventions.

  • 216.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Anti-angiogenic effects of tamoxifen in breast cancer by decreased secretion and reduced nuclear accumulation of angiogenin2009Inngår i: CANCER RESEARCH ISSN 0008-5472: Volume 69 Issue 2, 2009, Vol. 69, nr 2, s. 115S-115SKonferansepaper (Fagfellevurdert)
  • 217.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jill A.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Tamoxifen decreases extracellular TGF-beta 1 secreted from breast cancer cells - A post-translational regulation involving matrix metalloproteinase activity2009Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 315, nr 1, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transforming growth factor-beta 1 (TGF-beta 1) promotes cancer progression by regulating tumor cell growth and angiogenesis and high levels of TGF-beta 1 have been associated with metastatic disease and poor prognosis in breast cancer patients. We have previously reported anti-angiogenic effects of the anti-estrogen tamoxifen in breast cancer, by increased matrix metalloproteinase-9 (MMP-9) activity and generation of endostatin. Here, we show that exposure of tamoxifen to ER-positive breast cancer cells for 7 days, decreased extracellular TGF-beta 1. Intracellular TGF-beta 1 levels were unaffected by tamoxifen treatment, indicating a post-translational regulation of TGF-beta 1. Inhibition of MMP activity restored TGF-beta 1 levels, suggesting an involvement of MMP activities in the down-regulation of TGF-beta 1 by tamoxifen. Moreover, using an in vivo model of solid MCF-7 tumors in nude mice, we analyzed tumor levels of TGF-beta 1 after in vivo treatment with estradiol and tamoxifen. Exposure of tumor-bearing mice to tamoxifen significantly decreased tumor TGF-beta 1 protein levels, tumor growth and angiogenesis. In conclusion, our findings suggest a novel mechanism of action of tamoxifen in breast cancer via sex steroid dependent modulation of the proteolytic tumor microenvironment resulting in reduced extracellular TGF-beta 1 levels.

  • 218.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Saarinen, Niina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Nurmi, Tarja
    University of Eastern Finland.
    Engblom, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Tamoxifen and Flaxseed Alter Angiogenesis Regulators in Normal Human Breast Tissue In Vivo2011Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The incidence of breast cancer is increasing in the Western world and there is an urgent need for studies of the mechanisms of sex steroids in order to develop novel preventive strategies. Diet modifications may be among the means for breast cancer prevention. Angiogenesis, key in tumor progression, is regulated by the balance between pro-and anti-angiogenic factors, which are controlled in the extracellular space. Sampling of these molecules at their bioactive compartment is therefore needed. The aims of this study were to explore if tamoxifen, one of the most used anti-estrogen treatments for breast cancer affected some of the most important endogenous angiogenesis regulators, vascular endothelial growth factor (VEGF), angiogenin, and endostatin in normal breast tissue in vivo and if a diet supplementation with flaxseed had similar effects as tamoxifen in the breast. Microdialysis was used for in situ sampling of extracellular proteins in normal breast tissue of women before and after six weeks of tamoxifen treatment or before and after addition of 25 g/day of ground flaxseed to the diet or in control women. We show significant correlations between estradiol and levels of VEGF, angiogenin, and endostatin in vivo, which was verified in ex vivo breast tissue culture. Moreover, tamoxifen decreased the levels of VEGF and angiogenin in the breast whereas endostatin increased significantly. Flaxseed did not alter VEGF or angiogenin levels but similar to tamoxifen the levels of endostatin increased significantly. We conclude that one of the mechanisms of tamoxifen in normal breast tissue include tipping of the angiogenic balance into an anti-angiogenic state and that flaxseed has limited effects on the pro-angiogenic factors whereas the anti-angiogenic endostatin may be modified by diet. Further studies of diet modifications for breast cancer prevention are warranted.

  • 219.
    Nilsson, Ulrika W.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Effects of sex steroids and tamoxifen on matrix metalloproteinase activity and generation of endostatin in the breast2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Sex steroids are inevitable in women. However, long-term exposure to sex steroids increases the risk of breast cancer. A complete understanding of sex steroid control of the breast and how it relates to breast cancer risk is still lacking. Angiogenesis and proteolytic enzyme activity are crucial for the process by which tumors evolve into a vascularized, invasive phenotype. Matrix metalloproteinases are potent matrixdegrading enzymes that affect several steps in tumor progression including angiogenesis. In the female reproductive organs, sex steroids regulate angiogenesis and MMP activity, yet little is known how sex steroids affect these crucial events in normal and malignant breast tissue.

    This thesis elucidates a link between sex steroids, MMP activity, and angiogenesis. It is shown that estradiol down-regulates while tamoxifen up-regulates the protein expression and activity of MMP-2 and MMP-9 in human breast cancer cells in vitro and in human breast cancer xenografts in vivo. The results further suggest that a biological consequence of this regulation may be modulation of tumor angiogenesis. The net effect of adding tamoxifen to estradiol treatment was an increase in extracellular levels of the endogenous angiogenesis inhibitor endostatin and decreased levels of the tumor promoter TGF-β1 compared to estradiol treatment only. This was accompanied by reduced vasculature and decreased tumor growth. Similarly, a regulatory effect of estradiol and tamoxifen on endostatin generation was observed in normal human breast tissue by whole-tissue culture and microdialysis in human breast tissue in situ.

    In conclusion, the results presented in this thesis suggest previously unknown mechanisms of action of estradiol and tamoxifen in breast cancer and in normal human breast tissue, and novel means by which estradiol may tip the scale to favor angiogenesis. This knowledge may be important for the understanding of sex steroid dependent breast carcinogenesis and in the future development of tissue-specific preventive as well as therapeutic strategies against breast cancer.

    Delarbeid
    1. MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells
    Åpne denne publikasjonen i ny fane eller vindu >>MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells
    2007 (engelsk)Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, Vol. 102, nr 3, s. 253-261Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

    Emneord
    Breast cancer, Endostatin, Estrogen, Matrix metalloproteinases, Tamoxifen, Tissue inhibitors of matrix metalloproteinases, MCF-7 cells
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14550 (URN)10.1007/s10549-006-9335-4 (DOI)
    Tilgjengelig fra: 2007-05-30 Laget: 2007-05-30 Sist oppdatert: 2009-08-20
    2. Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo
    Åpne denne publikasjonen i ny fane eller vindu >>Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo
    2006 (engelsk)Inngår i: Cancer Research, ISSN 0008-5472, Vol. 66, nr 9, s. 4789-4794Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell–generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14551 (URN)10.1158/0008-5472.CAN-05-4012 (DOI)
    Tilgjengelig fra: 2007-05-30 Laget: 2007-05-30 Sist oppdatert: 2009-05-28
    3. Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo
    Åpne denne publikasjonen i ny fane eller vindu >>Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo
    2007 (engelsk)Artikkel i tidsskrift (Fagfellevurdert) Submitted
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14552 (URN)
    Tilgjengelig fra: 2007-05-30 Laget: 2007-05-30
    4. Estradiol decreases endostatin levels in normal human breast tissue in vivo
    Åpne denne publikasjonen i ny fane eller vindu >>Estradiol decreases endostatin levels in normal human breast tissue in vivo
    Manuskript (Annet vitenskapelig)
    Identifikatorer
    urn:nbn:se:liu:diva-14553 (URN)
    Tilgjengelig fra: 2007-05-30 Laget: 2007-05-30 Sist oppdatert: 2010-01-13
  • 220.
    Nilsson, Ulrika W.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo2006Inngår i: Cancer Research, ISSN 0008-5472, Vol. 66, nr 9, s. 4789-4794Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell–generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.

  • 221.
    Nilsson, Ulrika W.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells2007Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, Vol. 102, nr 3, s. 253-261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

  • 222.
    Nilsson, Ulrika W.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, J. A.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo2007Artikkel i tidsskrift (Fagfellevurdert)
  • 223.
    Niméus-Malmström, Emma
    et al.
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Krogh, Morten
    Computational Biology and Biological Physics, Department of Theoretical Physics, Lund University, Lund, Sweden .
    Malmström, Per
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Strand, Carina
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Fredriksson, Irma
    Department of Surgery, Karolinska University Hospital in Solna, Stockholm, Sweden .
    Karlsson, Per
    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Östberg, Görel
    Department of Pathology, Halmstad Hospital, Halmstad, Sweden .
    Peterson, Carsten
    Computational Biology and Biological Physics, Department of Theoretical Physics, Lund University, Lund, Sweden .
    Ferno, Marten
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy2008Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 10, nr 2Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction

    Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.

    Methods

    We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.

    Results

    Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-).

    Conclusion

    A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.

  • 224.
    Nordigården, Amanda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Zetterblad, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Trinks, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Druid, Pia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Ronnstrand, Lars
    Lund University.
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice2011Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, nr 2, s. 198-208Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

  • 225.
    Oakman, C
    et al.
    Hospital Prato, Italy .
    Francis, P A.
    Peter MacCallum Cancer Centre, Australia .
    Crown, J
    Irish Clin Oncology Research Grp, Ireland .
    Quinaux, E
    Int Institute Drug Dev, Belgium .
    Buyse, M
    Int Institute Drug Dev, Belgium .
    De Azambuja, E
    University of Libre Brussels, Belgium .
    Margeli Vila, M
    Hospital Badalona Germans Trias and Pujol, Spain .
    Andersson, M
    Danish Breast Cancer Cooperat Grp, Denmark .
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jakesz, R
    Vienna Medical Sch, Austria .
    Thuerlimann, B
    Kantonsspital, Switzerland .
    Gutierrez, J
    Clin Las Condes, Chile .
    Harvey, V
    Auckland City Hospital, New Zealand .
    Punzalan, L
    University of Libre Brussels, Belgium .
    DellOrto, P
    University of Milan, Italy .
    Larsimont, D
    University of Libre Brussels, Belgium .
    Steinberg, I
    Sanofi Oncol, England .
    Gelber, R D.
    IBCSG, MA USA .
    Piccart-Gebhart, M
    University of Libre Brussels, Belgium .
    Viale, G
    University of Milan, Italy .
    Di Leo, A
    Hospital Prato, Italy .
    Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer-8-year results of the Breast International Group 02-98 phase III trial2013Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, nr 5, s. 1203-1211Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. less thanbrgreater than less thanbrgreater thanMethods: Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) x 4 -andgt; classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) x 4 -andgt; CMF; (iii) sequential docetaxel: A (75 mg/m(2)) x3 -andgt; docetaxel (T) (100 mg/m(2)) x3. CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) x 4 -andgt; CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. less thanbrgreater than less thanbrgreater thanResults: Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. less thanbrgreater than less thanbrgreater thanConclusion: With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.

  • 226.
    Olsson, Hans
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Monsef, Nastaran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Johanson, Staffan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Immunohistochemical Evaluation of Cell Cycle Regulators: Impact on Predicting Prognosis in Stage T1 Urinary Bladder Cancer2012Inngår i: ISRN Urology, ISSN 2090-5807, E-ISSN 2090-5815, Vol. 2012, artikkel-id 379081Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background and Objective. The cell cycle is regulated by proteins at different checkpoints, and dysregulation of this cycle plays a role in carcinogenesis. Matrix metalloproteinases (MMPs) are enzymes that degrade collagen and promote tumour infiltration. The aim of this study was to evaluate the expression of various cell cycle regulators and MMPs, and to correlate such expression with progression and recurrence in patients with stage T1 urothelial carcinoma of the bladder (UCB).

    Patients and Methods. This population-based cohort study comprised 201 well-characterized patients with primary stage T1 urothelial carcinoma of the bladder. Immunohistochemistry was performed on formalin-fixed material to quantify expression of cell cycle regulators and two MMPs.

    Results. Normal expression of p53 and abnormal expression of MMP9 were associated with greater risk of tumour recurrence. Also, normal p16 expression was related to a lower risk of tumour progression. MMP2, p21, cyclin D1, and pRb showed no significant results that could estimate progression or recurrence.

    Conclusions. Normal p16 expression is associated with a lower risk of tumour progression, but immunohistochemistry on cell cycle regulators and MMPs has little value in predicting the prognosis in stage T1 UCB.

  • 227.
    Olsson, Hans
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Jahnson, Staffan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours2013Inngår i: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 47, nr 3, s. 188-195Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. Stage T1 urothelial carcinoma of the bladder (UCB) exhibits heterogeneous clinical behaviour, and the treatment is controversial. The aim of this study was to evaluate prognostic factors for UCB in a defined, population-based cohort comprising patients with a first time diagnosis of primary stage T1 UCB.

    Material and methods. The study population initially consisted of 285 patients with primary stage T1 UCB reported to the regional Bladder Cancer Registry in the Southeast Healthcare Region of Sweden from 1992 to 2001. The histological specimens were re-evaluated concerning stage, substaging of T1, World Health Organization (WHO) grade, lymphovascular invasion (LVI), tumour volume and total resected volume. Hospital records provided data on tumour size and multiplicity, occurrence of possible relapse and/or progression, death from UCB and whether treatment was given.

    Results. After re-evaluation, the study population comprised 211 patients. The median follow-up time was 60 months. LVI was a prognostic factor for UCB progression and recurrence. Tumour size larger than 30 mm and multiplicity increased the risk of recurrence. T1 substaging, tumour volume and total resected volume were not associated with recurrence or tumour progression.

    Conclusions. LVI is significantly correlated with progression and recurrence in patients with primary stage T1 UCB. Therefore, the presence of LVI should be evaluated in every new case of T1 UCB.

  • 228.
    Olsson, Hans
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk genetik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Methods for evaluating HER2 status in breast cancer: comparison of IHC, FISH, and real-time PCR analysis of formalin-fixed paraffin-embedded tissue2013Inngår i: Pathology and Laboratory Medicine International, ISSN 1179-2698, Vol. 5, s. 31-37Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The human epidermal growth factor receptor 2 gene (HER2) is amplified in approximately 15%–20% of all breast cancers. This results in overexpression of the HER2 protein, which is associated with worse clinical outcomes in breast cancer patients. Several studies have shown that trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor, can improve overall survival in patients with HER2-positive breast cancer. Immunohistochemistry (IHC), combined with different methods for in situ hybridization, is currently used for routine assessment of HER2 status. The aim of the present study was to determine whether real-time polymerase chain reaction (PCR) can serve as a supplementary method for evaluation of HER2 status in primary breast cancer. For this purpose, 145 formalin-fixed paraffin-embedded primary breast cancer samples were tested by real-time PCR amplification of HER2, using amyloid precursor protein as a reference. The results were compared with HER2 status determined by fluorescence in situ hybridization (FISH) and IHC. The specificity, sensitivity, and reproducibility of real-time PCR were evaluated, and a comparison of formalin-fixed and fresh-frozen samples was performed. This showed concordance of 93% between real-time PCR and FISH, and 86% between real-time PCR and IHC. Therefore, we suggest that real-time PCR can be a useful supplementary method for assessment of HER2 status.

  • 229.
    Olsson, Hans
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Jahnson, Staffan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T12013Inngår i: BMC Urology, ISSN 1471-2490, E-ISSN 1471-2490, Vol. 13, nr 5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Urinary bladder carcinoma stage T1 is an unpredictable disease that in some cases has a good prognosis with only local or no recurrence, but in others can appear as a more aggressive tumor with progression to more advanced stages. The aim here was to investigate stage T1 tumors regarding MDM2 promoter SNP309 polymorphism, mutations in the p53 gene, and expression of p53 and p16 measured by immunohistochemistry, and subsequently relate these changes to tumor recurrence and progression. We examined a cohort of patients with primary stage T1 urothelial carcinoma of the bladder and their tumors.

    Methods: After re-evaluation of the original slides and exclusions, the study population comprised 141 patients, all with primary stage T1 urothelial carcinoma of the bladder. The hospital records were screened for clinical parameters and information concerning presence of histologically proven recurrence and progression. The paraffin-embedded tumor material was evaluated by immunohistochemistry. Any mutations found in the p53 gene were studied by single-strand conformation analysis and Sanger sequencing. The MDM2 SNP309 polymorphism was investigated by pyrosequencing. Multivariate analyses concerning association with prognosis were performed, and Kaplan-Meier analysis was conducted for a combination of changes and time to progression.

    Results: Of the 141 patients, 82 had at least one MDM2 SNP309 G allele, and 53 had a mutation in the p53 gene, but neither of those anomalies was associated with a worse prognosis. A mutation in the p53 gene was associated with immunohistochemically visualized p53 protein expression at a cut-off value of 50%. In the group with p53 mutation Kaplan-Meier analysis showed higher rate of progression and shorter time to progression in patients with immunohistochemically abnormal p16 expression compared to them with normal p16 expression (p = 0.038).

    Conclusions: MDM2 SNP309 promoter polymorphism and mutations in p53 were not associated with worse prognosis in this cohort of patients with primary stage T1 urinary bladder carcinoma. However, patients with abnormal p16 expression and a mutated p53 gene had a higher rate of and a shorter time to progression, and p53 gene mutation was associated with an abnormal immunohistochemistry for p53 at a cut-off of 50%.

  • 230.
    Omar, H
    et al.
    Karolinska Institute.
    Hagglund, H
    Karolinska Institute.
    Johansson, J-E
    Sahlgrenska.
    Remberger, M
    Karolinska Institute.
    Kinch, A
    Uppsala University.
    Lazarevic, V
    Lund University.
    Wallin, A
    Umea University.
    Malm, C
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Machaczka, M
    Karolinska Institute.
    Hallbook, H
    Uppsala University.
    Juliusson, G
    Lund University.
    Ljungman, P
    Karolinska Institute.
    Kimby, E
    Karolinska Institute.
    High risk of PTLD development in lymphoma patients undergoing allogeneic haematopoietic stem cell transplantation in BONE MARROW TRANSPLANTATION, vol 46, issue , pp S328-S3282011Inngår i: BONE MARROW TRANSPLANTATION, Nature Publishing Group , 2011, Vol. 46, s. S328-S328Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 231.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    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/BRCA22011Inngår i: BRITISH JOURNAL OF CANCER, ISSN 0007-0920, Vol. 104, nr 8, s. 1356-1361Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 232.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    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)2009Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, nr 12, s. 2048-2054Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 233.
    Perez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Berglund, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Esguerra Merca, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Rutqvist, Lars Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Institutionen för cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål , Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer2006Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 28, nr 5, s. 1031-1042Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    P21WAF1/Cip1 (p21) translocates to the cytoplasm inducing cell cycle progression and survival upon Akt/PKB activation. We studied whether heregulin beta1 (HRGbeta1), that activates the PI3K/Akt and MAPK pathways, also misallocates p21. We also explored whether HRGbeta1 interferes with the effects of tamoxifen. The clinical material studied helped us to clarify whether p21 was associated with phosphorylated Akt, recurrence-free survival and response to tamoxifen. MCF-7 cells treated with HRGbeta1 -/+ E2 were analyzed by flow cytometry to observe how the different compounds affected tamoxifen-induced cell cycle arrest and apoptosis. Total cell lysate and nuclear and cytoplasmic fractions were used to detect p21, phospho-Akt and other proteins by Western blotting. Immunofluorescence was used to visualize p21+ cells upon HRGbeta1 and E2 stimulation. The localization of p21 in breast cancer was studied by immunohistochemistry in frozen tumor sections from 280 patients. In MCF-7 we found that HRGbeta1 counteracted the inhibition of p21 expression by tamoxifen and caused p21 cytoplasmic accumulation. HRGbeta1 partially counteracted the cytostatic effect of tamoxifen but abrogated its cytotoxic effect. The clinical material revealed that nuclear p21 (P=0.022) and cytoplasmic p21 (P=0.00001) were associated with phospho-Akt. Based on p21 cell location, we identified 3 subgroups of ER+ patients: the p21N+/C- group for whom tamoxifen was needed otherwise the survival was poor (P=0.0082), the p21N+/C+ or p21N-/C- group, that responded to tamoxifen (P=0.034), and the p21C+/N- group, that might not benefit from this treatment (P=0.7). In conclusion, HRGbeta1 inhibits tamoxifen-induced apoptosis, contributes to p21 cytoplasmic expression while the cellular localization of p21 interacts with the benefit from tamoxifen treatment.

  • 234.
    Perez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Elin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Ahnström, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fornander, Tommy
    Karolinska University Hospital, Department Oncol, S-11883 Stockholm, Sweden.
    Skoog, Lambert
    Karolinska University Hospital, Department Pathol and Cytol, S-17176 Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer2011Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 128, nr 3, s. 713-723Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.

  • 235.
    Perez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ahnström Waltersson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Department of Cytology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer2008Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates the ribosomal S6 kinases (S6K)1 and 2 integrate nutrient and hormonal/growth factor mediated signals and are implicated indiabetes, obesity and cancer. The genes encoding S6K1 (RPS6KB1) and S6K2 (RPS6KB2) aresituated close to well known amplicons but information regarding its expression and clinicalvalue is scarce. In this study we quantified RPS6KB1/2 gene copy number, establishedassociations with other clinical factors and explored their clinical value in breast cancer. RPS6KB1/2 copy number was determined by fast real-time PCR in 207 breast tumors.RPS6KB1 was amplified (≥ 4 copies) in 10.7% (22/206) and RPS6KB2 in 4.3% (9/207) of thetumors. Amplification of RPS6KB1 was associated with HER2 gene amplification (P=0.025)and protein expression (P=0.014) while RPS6KB2 correlated with ER+ status (P=0.046) and CCND1 amplification (P<0.00001). In a multivariate analysis, both genes were independentprognostic factors indicating higher risk to develop recurrences. In terms of loco regionalcontrol, amplification of the RPS6KB1 gene predicted less response to radiotherapy (P=0.035) while RPS6KB2 gene copy gain (≥ 3 copies) indicated increased benefit from tamoxifen (P=0.03) among ER+ patients. S6K1/2 gene amplification could be used as an indicator oftherapy response among postmenopausal breast cancer patients.

  • 236. Pestalozzi, B. C.
    et al.
    Francis, P.
    Quinaux, E.
    Dolci, S.
    Azambuja, E.
    Gelber, R. D.
    Viale, G.
    Balil, A.
    Andersson, M.
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gnant, M.
    Gutierrez, J.
    Láng, I.
    Crown, J. P. A.
    Piccart-Gebhart, M.
    Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup phase III BIG 02-98 trial2008Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 19, nr 11, s. 1837-1841Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. Patients and methods: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. Results: CNS relapse occurred in 4.0% of control patients and3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. Conclusion: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

  • 237.
    Pfeifer, Daniella
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    p73 in colorectal cancer2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Colorectal cancer (CRC) is the third most common cancer in the world, with about 5000 new cases in Sweden every year. CRC is caused by mutation (inherited or acquired) in genes, by gene variants and changed expression of proteins. The primary way to achieve a curative result for CRC is to remove the tumor by surgery. To reduce risk of recurrence chemo- or radiotherapy are given as a complement to surgery. p73 is a structural and functional homologue of tumor suppressor p53. However, p73 is rarely mutated in tumors, but rather overexpressed as compared to normal tissue. There are two main isoforms of p73, the transactivation capable TAp73 and the truncated ΔNp73, which are involved in an autoregulatory loop with TAp73 and p53.

    The aim of this study was to investigate the role of p73 and related proteins in the development and treatment of CRC. A G4C14-to-A4T14 polymorphism of p73 was studied in CRC patients and healthy controls (Paper I), and rectal cancer patients who were randomized to treatment with either surgery alone or preoperative radiotherapy and surgery (Paper II). The AT/AT genotype of the p73 polymorphism may increase risk of CRC development and CRC patients with the AT allele had a better prognosis. When dividing the cases into colon and rectal cancer it was seen that in colon cancer the AT allele tended to be more favorable for overall survival, while in rectal cancer the GC allele seemed to be more favorable. Rectal cancer patients, with a combination of GC/GC genotype, wild type p53 and weak survivin expression survived longer after preoperative radiotherapy. This was not observed in the patients only receiving surgery. The protein expression of p73 was further studied in the rectal cancer patients randomized to treatment with either surgery alone or preoperative radiotherapy and surgery (Paper III). p73 was expressed higher in tumor tissue than in normal mucosa. Patients with p73 negative tumors had a lower risk of local recurrence after radiotherapy, as opposed to patients that had p73 positive tumors or patients with p73 negative tumors that did not receive radiotherapy. Effects of γ-radiation was further studied in colon cancer cell lines KM12C, KM12SM and KM12L4a regarding cell cycle, survival fraction (clonogenicity), apoptosis and protein expression patterns of mutated p53, TAp73, ΔNp73, survivin and PRL-3 (Paper IV). KM12C displayed low survival fraction, low apoptosis, no cell cycle arrest and an upregulation of the antiapoptotic ΔNp73 after irradiation. KM12L4a showed a high survival fraction, but high apoptosis, arresting of the cell cycle and upregulation of the radio-resistance factor survivin. The effects of overexpression and knockdown of survivin on TAp73, ΔNp73 and p53 expression in colon cancer cell lines HCT-116p53+/+ and HCT-116p53-/- with and without γ-radiation were studied (Paper V). Overexpression of survivin decreased wild type p53, whilst downregulation of survivin lead to a simultaneous downregulation of TAp73 and ΔNp73, mRNA and protein, both with and without γ- radiation. Knockdown of survivin also demonstrated an increase in apoptosis.

    In conclusion, we showed that the G4C14-to-A4T14 polymorphism of p73 and p73 protein expression may be involved in CRC development, radiotherapy response and survival. We further showed that TAp73, ΔNp73 and p53 were regulated by survivin in colon cancer cells.

    Delarbeid
    1. Polymorphism of the p73 gene in relation to colorectal cancer risk and survival
    Åpne denne publikasjonen i ny fane eller vindu >>Polymorphism of the p73 gene in relation to colorectal cancer risk and survival
    2005 (engelsk)Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 26, nr 1, s. 103-107Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The results regarding a GC/AT polymorphism in the p73 gene in relation to cancer risk are inconsistent, and the significance of loss of heterozygosity (LOH) of the gene is unclear. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. 179 patients with colorectal cancer and 260 healthy controls were genotyped for the polymorphism by PCR-restriction fragment length polymorphism (RFLP). Fifty informative cases were examined for LOH in tumours. Immunohistochemistry was performed on distant (n = 42) and adjacent normal mucosa (n = 33), primary tumour (n = 6 9) and lymph node metastasis (n = 12). The frequencies of the genotypes were 63% for wild-type (GC/GC), 30% for heterozygotes (GC/AT) and 7% for variants (AT/AT) in patients, and 62, 36 and 2% in controls, respectively. The frequencies of the genotypes in the patients and controls were significantly different (P = 0.02). The patients carrying the AT allele had a better prognosis than those with the GC/GC genotype (OR = 0.42, 95% CI = 1.15-5.02, P = 0.02). No LOH was observed at the p73 locus. Expression of p73 protein was increased from normal mucosa to primary tumours (P = 0.02), but was not significantly changed between primary tumours and metastases (P = 1.0). In conclusion, the AT/AT homozygotes may have a greater risk of developing colorectal cancer, while the patients who carried the AT allele had a better prognosis.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-18428 (URN)10.1093/carcin/bgh305 (DOI)15485994 (PubMedID)
    Tilgjengelig fra: 2009-05-26 Laget: 2009-05-26 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy
    2009 (engelsk)Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 92, nr 2, s. 215-220Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background and Purpose: An exon 2 G4C14→A4T14 polymorphism in the p73 gene was shown to be related to survival in several types of cancers, including colorectal cancer. The purpose was to investigate if this polymorphism was related to survival in rectal cancer patients with or without preoperative radiotherapy.

    Material and Methods: DNA extracted from tissue of 138 rectal cancer patients that received preoperative radiotherapy or had surgery alone was typed for the polymorphism by PCR using confronting two-pair primers.

    Results: Among patients, 69% had GC/GC genotype, 27% GC/AT and 4% AT/AT. In the radiotherapy group, patients carrying the AT (GC/AT+AT/AT) allele had stronger expression of p53 (p=0.001) and survivin protein (p=0.03) than those carrying the GC/GC genotype. Further, among patients receiving preoperative radiotherapy the GC/GC genotype tended to be related to better survival (p=0.20). Patients with GC/GC genotype, along with negative p53 and weak survivin expression showed better survival than the other patients (p=0.03), even after adjusting for TNM stage and tumor differentiation (p=0.01, RR, 7.63, 95% CI, 1.50-38.74). In the non-radiotherapy group, the polymorphism was not related to survival (p=0.74).

    Conclusions: Results suggest that the p73 G4C14→A4T14 polymorphism could be one factor influencing outcome of preoperative radiotherapy in rectal cancer patients.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-18429 (URN)10.1016/j.radonc.2009.06.007 (DOI)
    Merknad
    Original Publication: Jasmine Lööf, Daniella Pfeifer, Gunnar Adell and Xiao-Feng Sun, Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy, 2009, Radiotherapy and Oncology, (92), 2, 215-220. http://dx.doi.org/10.1016/j.radonc.2009.06.007 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Tilgjengelig fra: 2009-09-09 Laget: 2009-05-26 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    3. Expression of the p73 protein in rectal cancers with or without preoperative radiotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>Expression of the p73 protein in rectal cancers with or without preoperative radiotherapy
    2006 (engelsk)Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 65, nr 4, s. 1143-1148Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: To investigate p73 expression in normal mucosa, primary tumor, and metastasis in relation to radiotherapy (RT) response and clinicopathologic/biologic variables in rectal cancers.

    Methods and Materials: p73 was immunohistochemically examined on biopsies (unirradiated, n = 102), distant (from the large bowel, n = 82), and adjacent (adjacent to primary tumor, n = 89) normal mucosa samples, primary tumors (n = 131), and lymph node metastasis (n = 32) from rectal cancer patients participating in a clinical trial of preoperative RT. Seventy-four patients received surgery alone and 57 received additional RT.

    Results: Cytoplasmic p73 was increased in the primary tumor compared with the distant or adjacent mucosa (p ≤ 0.0001). Nuclear (p = 0.02) and cytoplasmic (p = 0.003) p73 was higher in irradiated distant mucosa samples than in unirradiated ones, and nuclear p73 tended to be increased in irradiated primary tumors compared with unirradiated ones (p = 0.06). p73 was positively related to cyclooxygenase-2 expression in irradiated tumors (p = 0.03). p73-negative tumors tended to have a lower local recurrence after RT compared with unirradiated cases (p = 0.06).

    Conclusions: Normal epithelial cells seem more sensitive to RT than tumor cells regarding p73 expression. Patients with p73-negative rectal tumors may have a lower risk of local recurrence after RT.

    sted, utgiver, år, opplag, sider
    Elsevier, 2006
    Emneord
    p73; Radiotherapy; Local recurrence; Rectal cancer; Immunohistochemistry
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-18430 (URN)10.1016/j.ijrobp.2006.02.028 (DOI)16750334 (PubMedID)
    Tilgjengelig fra: 2009-05-26 Laget: 2009-05-26 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    4. Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p53
    Åpne denne publikasjonen i ny fane eller vindu >>Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p53
    2009 (engelsk)Inngår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 135, nr 11, s. 1583-1592Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We previously found that p53, p73, survivin and PRL were implicated in the outcome of radiotherapy in rectal cancer patients. In the present study, we tried to understand mechanisms of colon cancer cell line response to radiation based on protein expression related to proliferation and apoptosis. KM12C, KM12SM and KM12L4a, cell lines with one origin, were radiated with 0, 10 or 15 Gy γ-radiation. Radiosensitivity was determined with cell cycle and apoptosis analysis, and protein expression of TAp73, ΔNp73, mutated p53, survivin and PRL-3 was determined by Western blot. KM12C showed transient G2-arrest, low apoptosis and up-regulation of resistance factors such as PRL-3. In KM12C expression of ΔNp73 increased after 10Gy, but not after 15Gy. KM12SM had permanent G2-arrest, low apoptosis and showed up-regulation of the anti-apoptotic survivin and down-regulation of the pro-apoptotic TAp73 and the radioresistance factor PRL-3 was down-regulated. KM12L4a, the most radiosensitive cell line, showed up-regulation of TAp73 and down-regulation/no up-regulation of resistance factors such as ΔNp73, survivin and PRL-3 after radiation. In conclusion, the KM12C cell line was more radioresistant than KM12L4a regarding apoptosis and certain apoptotic proteins. The radiosensitivity of KM12L4a might partly depend on the lack of up-regulation of proteins negative for the outcome of radiotherapy.

     

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14786 (URN)10.1007/s00432-009-0606-4 (DOI)
    Tilgjengelig fra: 2008-09-24 Laget: 2008-09-24 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    5. Survivin regulates expression of p73 isoforms TAp73 and ΔNp73 in colon cancer cell lines with and without γ-radiation
    Åpne denne publikasjonen i ny fane eller vindu >>Survivin regulates expression of p73 isoforms TAp73 and ΔNp73 in colon cancer cell lines with and without γ-radiation
    (engelsk)Manuskript (Annet vitenskapelig)
    Abstract [en]

    Wild type p53 represses expression of survivin, however little is known if survivin regulates p53 and the two isoforms of the p53 homologue p73, TAp73 and ΔNp73. The aim of our study was to investigate a possible connection between survivin and TAp73 and ΔNp73 in colon cancer cell lines HCT-116p53+/+ and HCT- 116p53-/- with and without γ-irradiation. HCT-116p53+/+ and HCT-116p53-/- were transfected with either survivin cDNA or siRNA against survivin. Cells transfected with siRNA were irradiated with 0Gy or 4Gy γ-irradiation to induce DNA-damage. Expression levels of survivin, TAp73, ΔNp73, mRNA and protein, and p53 protein was measured by RT-PCR and Western blot. Apoptosis was measured by means of M30- Apoptosense™ Elisa. Over-expression of survivin did not significantly change TAp73 or ΔNp73 mRNA and protein, whilst wild type p53 decreased. When survivin was knocked down, mRNA and protein of TAp73 and ΔNp73 decreased, both with and without γ-irradiation. Knockdown of survivin increased apoptosis in both HCT-116 cell lines with and without γ-irradiation. Knockdown of survivin decreased levels of TAp73 and ΔNp73 in both HCT-116p53+/+ and HCT-116p53-/-, and caused an increase in apoptosis, especially noticeable in HCT-116p53-/- after irradiation. Survivin down-regulation did not seem to affect the levels of wild type p53, whilst an up-regulation of survivin down-regulated wild type p53.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-18431 (URN)
    Tilgjengelig fra: 2009-05-26 Laget: 2009-05-26 Sist oppdatert: 2010-01-14bibliografisk kontrollert
  • 238.
    Pfeifer, Daniella
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Xiao-Feng , Sun
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Survivin regulates expression of p73 isoforms TAp73 and ΔNp73 in colon cancer cell lines with and without γ-radiationManuskript (Annet vitenskapelig)
    Abstract [en]

    Wild type p53 represses expression of survivin, however little is known if survivin regulates p53 and the two isoforms of the p53 homologue p73, TAp73 and ΔNp73. The aim of our study was to investigate a possible connection between survivin and TAp73 and ΔNp73 in colon cancer cell lines HCT-116p53+/+ and HCT- 116p53-/- with and without γ-irradiation. HCT-116p53+/+ and HCT-116p53-/- were transfected with either survivin cDNA or siRNA against survivin. Cells transfected with siRNA were irradiated with 0Gy or 4Gy γ-irradiation to induce DNA-damage. Expression levels of survivin, TAp73, ΔNp73, mRNA and protein, and p53 protein was measured by RT-PCR and Western blot. Apoptosis was measured by means of M30- Apoptosense™ Elisa. Over-expression of survivin did not significantly change TAp73 or ΔNp73 mRNA and protein, whilst wild type p53 decreased. When survivin was knocked down, mRNA and protein of TAp73 and ΔNp73 decreased, both with and without γ-irradiation. Knockdown of survivin increased apoptosis in both HCT-116 cell lines with and without γ-irradiation. Knockdown of survivin decreased levels of TAp73 and ΔNp73 in both HCT-116p53+/+ and HCT-116p53-/-, and caused an increase in apoptosis, especially noticeable in HCT-116p53-/- after irradiation. Survivin down-regulation did not seem to affect the levels of wild type p53, whilst an up-regulation of survivin down-regulated wild type p53.

  • 239.
    Pfeifer, Daniella
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Polymorphism of the p73 gene in relation to colorectal cancer risk and survival2005Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 26, nr 1, s. 103-107Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The results regarding a GC/AT polymorphism in the p73 gene in relation to cancer risk are inconsistent, and the significance of loss of heterozygosity (LOH) of the gene is unclear. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. 179 patients with colorectal cancer and 260 healthy controls were genotyped for the polymorphism by PCR-restriction fragment length polymorphism (RFLP). Fifty informative cases were examined for LOH in tumours. Immunohistochemistry was performed on distant (n = 42) and adjacent normal mucosa (n = 33), primary tumour (n = 6 9) and lymph node metastasis (n = 12). The frequencies of the genotypes were 63% for wild-type (GC/GC), 30% for heterozygotes (GC/AT) and 7% for variants (AT/AT) in patients, and 62, 36 and 2% in controls, respectively. The frequencies of the genotypes in the patients and controls were significantly different (P = 0.02). The patients carrying the AT allele had a better prognosis than those with the GC/GC genotype (OR = 0.42, 95% CI = 1.15-5.02, P = 0.02). No LOH was observed at the p73 locus. Expression of p73 protein was increased from normal mucosa to primary tumours (P = 0.02), but was not significantly changed between primary tumours and metastases (P = 1.0). In conclusion, the AT/AT homozygotes may have a greater risk of developing colorectal cancer, while the patients who carried the AT allele had a better prognosis.

  • 240.
    Pfeifer, Daniella
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gao, Jingfang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Adell, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Expression of the p73 protein in rectal cancers with or without preoperative radiotherapy2006Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 65, nr 4, s. 1143-1148Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To investigate p73 expression in normal mucosa, primary tumor, and metastasis in relation to radiotherapy (RT) response and clinicopathologic/biologic variables in rectal cancers.

    Methods and Materials: p73 was immunohistochemically examined on biopsies (unirradiated, n = 102), distant (from the large bowel, n = 82), and adjacent (adjacent to primary tumor, n = 89) normal mucosa samples, primary tumors (n = 131), and lymph node metastasis (n = 32) from rectal cancer patients participating in a clinical trial of preoperative RT. Seventy-four patients received surgery alone and 57 received additional RT.

    Results: Cytoplasmic p73 was increased in the primary tumor compared with the distant or adjacent mucosa (p ≤ 0.0001). Nuclear (p = 0.02) and cytoplasmic (p = 0.003) p73 was higher in irradiated distant mucosa samples than in unirradiated ones, and nuclear p73 tended to be increased in irradiated primary tumors compared with unirradiated ones (p = 0.06). p73 was positively related to cyclooxygenase-2 expression in irradiated tumors (p = 0.03). p73-negative tumors tended to have a lower local recurrence after RT compared with unirradiated cases (p = 0.06).

    Conclusions: Normal epithelial cells seem more sensitive to RT than tumor cells regarding p73 expression. Patients with p73-negative rectal tumors may have a lower risk of local recurrence after RT.

  • 241.
    Pfeifer, Daniella
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Wallin, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p532009Inngår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 135, nr 11, s. 1583-1592Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We previously found that p53, p73, survivin and PRL were implicated in the outcome of radiotherapy in rectal cancer patients. In the present study, we tried to understand mechanisms of colon cancer cell line response to radiation based on protein expression related to proliferation and apoptosis. KM12C, KM12SM and KM12L4a, cell lines with one origin, were radiated with 0, 10 or 15 Gy γ-radiation. Radiosensitivity was determined with cell cycle and apoptosis analysis, and protein expression of TAp73, ΔNp73, mutated p53, survivin and PRL-3 was determined by Western blot. KM12C showed transient G2-arrest, low apoptosis and up-regulation of resistance factors such as PRL-3. In KM12C expression of ΔNp73 increased after 10Gy, but not after 15Gy. KM12SM had permanent G2-arrest, low apoptosis and showed up-regulation of the anti-apoptotic survivin and down-regulation of the pro-apoptotic TAp73 and the radioresistance factor PRL-3 was down-regulated. KM12L4a, the most radiosensitive cell line, showed up-regulation of TAp73 and down-regulation/no up-regulation of resistance factors such as ΔNp73, survivin and PRL-3 after radiation. In conclusion, the KM12C cell line was more radioresistant than KM12L4a regarding apoptosis and certain apoptotic proteins. The radiosensitivity of KM12L4a might partly depend on the lack of up-regulation of proteins negative for the outcome of radiotherapy.

     

  • 242.
    Polymeropoulos, MH
    et al.
    Novartis Pharmaceut Corp, Pharmacogenet, Gaithersburg, MD USA Linkoping Univ, Dept Biomed & Surg, Fac Hlth Sci, S-58185 Linkoping, Sweden.
    Baras, A
    Novartis Pharmaceut Corp, Pharmacogenet, Gaithersburg, MD USA Linkoping Univ, Dept Biomed & Surg, Fac Hlth Sci, S-58185 Linkoping, Sweden.
    Walz, Thomas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Kwon, I
    Novartis Pharmaceut Corp, Pharmacogenet, Gaithersburg, MD USA Linkoping Univ, Dept Biomed & Surg, Fac Hlth Sci, S-58185 Linkoping, Sweden.
    Dressman, MA
    Novartis Pharmaceut Corp, Pharmacogenet, Gaithersburg, MD USA Linkoping Univ, Dept Biomed & Surg, Fac Hlth Sci, S-58185 Linkoping, Sweden.
    Detecting gene amplification in breast cancer by combining Gene expression profiling and Gene mapping.2001Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 69, nr 4, s. 440-Konferansepaper (Annet vitenskapelig)
  • 243.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Alterations in the PI3K/AKT Signaling Pathway and Response to Adjuvant Treatment in Breast Cancer2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    (PI3K)/AKT signaling pathway could be a cause of therapeutic resistance in breast cancer. The PI3K/AKT pathway controls cell proliferation, cell growth and survival, and its members include oncogenes and tumor suppressor genes. Alterations in this pathway are frequent in cancer. In this thesis, we aimed to study the biological significance of some of these alterations in a tumor context as well as their clinical value. PIK3CA gene, encoding the PI3K catalytic subunit, was examined for mutations. The tumor suppressor PTEN, that counteracts PI3Kmediated effects, was studied at the protein level whereas amplification of RPS6KB1 (S6K1) and RPS6KB2 (S6K2) genes, encoding two substrates of the mammalian target of rapamycin (mTOR) acting downstream PI3K/AKT, was also inspected. AKT phosphorylation or activation (pAKT) was determined by immunohistochemistry. Other factors related with this pathway, such as HER-2, heregulin (HRG) β1, the cell cycle inhibitor p21WAF1/CIP1, the pro-apoptotic factor Bcl-2, and cyclin D1,  were also considered. These studies were perfomed in two patient materials consisting of premenopausal patients that received endocrine treatment (paper I) and postmenopausal patients randomized to receive radiotherapy (RT) or chemotherapy (CMF) in combination with tamoxifen (Tam) or no endocrine treatment (papers II-IV). In the first material, we found that pAKT indicated higher risk of distant recurrence among endocrine treated patients. In the second material HRGβ1 induced accumulation cytoplasmic p21 in vitro and pAKT was associated with cytoplasmic p21 in the tumors. In addition, p21 cellular location identified subgroups of ER+ patients with different responses to tamoxifen. Other alterations such as PIK3CA mutations and PTEN loss were positively associated in this material. PIK3CA mutations lowered the risk for local recurrences while PTEN loss conferred radiosensitivity as a single variable or combined with mutated PIK3CA. PIK3CA mutations and/or PTEN loss was associated with lower S-phase (SPF). Nevertheless, among patients with low proliferating tumors, these alterations predicted higher risk of recurrence in contrast to those with high proliferating tumors. Finally, we found amplification of the S6K1 and S6K2 genes. S6K2 amplification was associated with cyclin D1 gene amplification, predicted poor recurrence-free survival and breast cancer death, and indicated benefit from tamoxifen. On the other hand, S6K1 amplification was associated with HER-2 amplification/overexpression, indicated higher risk of recurrence and was a predictor of poor response to radiotherapy. These results indicate the potential of this pathway as therapeutic source.

     

    Delarbeid
    1. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients
    Åpne denne publikasjonen i ny fane eller vindu >>Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients
    2002 (engelsk)Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 86, nr 4, s. 540-545Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin β1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged < 50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P = 0.001) and the presence of heregulin β1-expressing stromal cells (P = 0.017). Neither Akt-1 nor pAkt was related with other factors Turnout cells-derived heregulin β1 was found mainly in oestrogen receptor negative (P = 0.026) and node negative (P = 0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P = 0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer

    Emneord
    Breast cancer, endocrine treatment, Akt, PKB, erbB-2, hergulin ß1
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-15031 (URN)10.1038/sj.bjc.6600126 (DOI)
    Tilgjengelig fra: 2008-10-10 Laget: 2008-10-10 Sist oppdatert: 2017-12-11
    2. Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer
    Vise andre…
    2006 (engelsk)Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 28, nr 5, s. 1031-1042Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    P21WAF1/Cip1 (p21) translocates to the cytoplasm inducing cell cycle progression and survival upon Akt/PKB activation. We studied whether heregulin beta1 (HRGbeta1), that activates the PI3K/Akt and MAPK pathways, also misallocates p21. We also explored whether HRGbeta1 interferes with the effects of tamoxifen. The clinical material studied helped us to clarify whether p21 was associated with phosphorylated Akt, recurrence-free survival and response to tamoxifen. MCF-7 cells treated with HRGbeta1 -/+ E2 were analyzed by flow cytometry to observe how the different compounds affected tamoxifen-induced cell cycle arrest and apoptosis. Total cell lysate and nuclear and cytoplasmic fractions were used to detect p21, phospho-Akt and other proteins by Western blotting. Immunofluorescence was used to visualize p21+ cells upon HRGbeta1 and E2 stimulation. The localization of p21 in breast cancer was studied by immunohistochemistry in frozen tumor sections from 280 patients. In MCF-7 we found that HRGbeta1 counteracted the inhibition of p21 expression by tamoxifen and caused p21 cytoplasmic accumulation. HRGbeta1 partially counteracted the cytostatic effect of tamoxifen but abrogated its cytotoxic effect. The clinical material revealed that nuclear p21 (P=0.022) and cytoplasmic p21 (P=0.00001) were associated with phospho-Akt. Based on p21 cell location, we identified 3 subgroups of ER+ patients: the p21N+/C- group for whom tamoxifen was needed otherwise the survival was poor (P=0.0082), the p21N+/C+ or p21N-/C- group, that responded to tamoxifen (P=0.034), and the p21C+/N- group, that might not benefit from this treatment (P=0.7). In conclusion, HRGbeta1 inhibits tamoxifen-induced apoptosis, contributes to p21 cytoplasmic expression while the cellular localization of p21 interacts with the benefit from tamoxifen treatment.

    Emneord
    PI3K, heregulin ß1, cell cycle, cell survival
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-15032 (URN)16596219 (PubMedID)
    Tilgjengelig fra: 2008-10-10 Laget: 2008-10-10 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    3. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
    Åpne denne publikasjonen i ny fane eller vindu >>PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
    Vise andre…
    2007 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 12, s. 3577-3584Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.

    Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.

    Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.

    Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-15041 (URN)10.1158/1078-0432.CCR-06-1609 (DOI)17575221 (PubMedID)
    Tilgjengelig fra: 2008-10-13 Laget: 2008-10-13 Sist oppdatert: 2017-12-11
    4. Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer
    Vise andre…
    2008 (engelsk)Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates the ribosomal S6 kinases (S6K)1 and 2 integrate nutrient and hormonal/growth factor mediated signals and are implicated indiabetes, obesity and cancer. The genes encoding S6K1 (RPS6KB1) and S6K2 (RPS6KB2) aresituated close to well known amplicons but information regarding its expression and clinicalvalue is scarce. In this study we quantified RPS6KB1/2 gene copy number, establishedassociations with other clinical factors and explored their clinical value in breast cancer. RPS6KB1/2 copy number was determined by fast real-time PCR in 207 breast tumors.RPS6KB1 was amplified (≥ 4 copies) in 10.7% (22/206) and RPS6KB2 in 4.3% (9/207) of thetumors. Amplification of RPS6KB1 was associated with HER2 gene amplification (P=0.025)and protein expression (P=0.014) while RPS6KB2 correlated with ER+ status (P=0.046) and CCND1 amplification (P<0.00001). In a multivariate analysis, both genes were independentprognostic factors indicating higher risk to develop recurrences. In terms of loco regionalcontrol, amplification of the RPS6KB1 gene predicted less response to radiotherapy (P=0.035) while RPS6KB2 gene copy gain (≥ 3 copies) indicated increased benefit from tamoxifen (P=0.03) among ER+ patients. S6K1/2 gene amplification could be used as an indicator oftherapy response among postmenopausal breast cancer patients.

    Emneord
    PI3K, AKT, mTOR, CCND1, HER2, ER, Tamoxifen
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-15042 (URN)
    Tilgjengelig fra: 2008-10-13 Laget: 2008-10-13 Sist oppdatert: 2009-04-09
  • 244.
    Pérez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Alkhori, Liza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Ahnstro Waltersson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Rutqvist, Lars Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Institutionen för Cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer2007Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 12, s. 3577-3584Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.

    Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.

    Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.

    Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

  • 245.
    Pérez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Members of the Southeast Sweden Breast Cancer Group,
    Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients2002Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 86, nr 4, s. 540-545Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin β1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged < 50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P = 0.001) and the presence of heregulin β1-expressing stromal cells (P = 0.017). Neither Akt-1 nor pAkt was related with other factors Turnout cells-derived heregulin β1 was found mainly in oestrogen receptor negative (P = 0.026) and node negative (P = 0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P = 0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer

  • 246.
    Qvortrup, C.
    et al.
    Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, Odense C 5000, Denmark, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
    Yilmaz, M.
    Department of Oncology, Aalborg University Hospital, Aalborg, Denmark.
    Ogreid, D.
    Department of Oncology, Rogaland Central Hospital, Stavanger, Norway.
    Berglund, A.
    Department of Oncology, Radiology and Clinical Immunology, University Hospital, Uppsala University Hospital, Uppsala, Sweden.
    Balteskard, L.
    Department of Oncology, Tromso University Hospital, Tromso, Norway.
    Ploen, J.
    Department of Oncology, Vejle Hospital, Vejle, Denmark.
    Fokstuen, T.
    Department of Oncology and Pathology, Karolinska Hospital, Stockholm, Sweden.
    Starkhammar, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Sorbye, H.
    Sørbye, H., Department of Oncology, Haukeland University Hospital, Bergen, Norway.
    Tveit, K.
    Department of Oncology, Ullevål University Hospital, Oslo, Norway.
    Pfeiffer, P.
    Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, Odense C 5000, Denmark.
    Chronomodulated capecitabine in combination with short-time oxaliplatin: A Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil2008Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 19, nr 6, s. 1154-1159Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Oxaliplatin in combination with capecitabine prolongs survival in patients with metastatic colorectal cancer (mCRC). Chronomodulation might reduce toxicity and improve efficacy. Patients and methods: A phase II study examining chronomodulated XELOX30 (XELOX30chron): oxaliplatin: 130 mg/m2 on day 1, as a 30-min infusion between 1 and 3 p.m. Capecitabine: total daily dose of 2000 mg/m2, 20% of the dose between 7 and 9 a.m. and 80% of the dose between 6 and 8 p.m. in patients with mCRC resistant to irinotecan. Seventy-one patients were enrolled. Response rate was 18%, median progression-free survival 5.1 months and median overall survival (OS) 10.2 months. Platelet count and performance status were significantly correlated to OS in multivariate analyses. Neurotoxicity grade 2 and 3 was seen in 25% and 2% of patients, respectively, other grade 3 toxic effects were as follows: nausea 6%, vomiting 3%, diarrhoea 12% (3% experienced grade 4) and palmoplantart erytem 9%. Conclusion: XELOX30chron is a convenient second-line regimen with efficacy and safety profile similar to other oxaliplatin schedules. To further investigate chronomodulated XELOX, we have started a Nordic randomised phase II study comparing XELOX30 and XELOX30chron as first-line therapy in patients with mCRC. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

  • 247. 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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    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.2012Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, nr 4, s. 690-702Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 248.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    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 Carriers2011Inngår i: JOURNAL OF THE NATIONAL CANCER INSTITUTE, ISSN 0027-8874, Vol. 103, nr 2Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 249.
    Razavi, Amir Reza
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatiK. Linköpings universitet, Tekniska högskolan.
    Gill, Hans
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatiK. Linköpings universitet, Tekniska högskolan.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sundquist, Marie
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Pathology, County Hospital, Kalmar, Sweden.
    Åhlfeldt, Hans
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatiK. Linköpings universitet, Tekniska högskolan.
    Shahsavar, Nosrat
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatiK. Linköpings universitet, Tekniska högskolan.
    The South-East Swedish Breast Cancer Study Group,
    Exploring cancer register data to find risk factors for recurrence of breast cancer: Application of Canonical Correlation Analysis2005Inngår i: BMC Medical Informatics and Decision Making, ISSN 1472-6947, Vol. 5, nr 29, s. 29-35Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    A common approach in exploring register data is to find relationships between outcomes and predictors by using multiple regression analysis (MRA). If there is more than one outcome variable, the analysis must then be repeated, and the results combined in some arbitrary fashion. In contrast, Canonical Correlation Analysis (CCA) has the ability to analyze multiple outcomes at the same time.

    One essential outcome after breast cancer treatment is recurrence of the disease. It is important to understand the relationship between different predictors and recurrence, including the time interval until recurrence. This study describes the application of CCA to find important predictors for two different outcomes for breast cancer patients, loco-regional recurrence and occurrence of distant metastasis and to decrease the number of variables in the sets of predictors and outcomes without decreasing the predictive strength of the model.

    Methods

    Data for 637 malignant breast cancer patients admitted in the south-east region of Sweden were analyzed. By using CCA and looking at the structure coefficients (loadings), relationships between tumor specifications and the two outcomes during different time intervals were analyzed and a correlation model was built.

    Results

    The analysis successfully detected known predictors for breast cancer recurrence during the first two years and distant metastasis 2–4 years after diagnosis. Nottingham Histologic Grading (NHG) was the most important predictor, while age of the patient at the time of diagnosis was not an important predictor.

    Conclusion

    In cancer registers with high dimensionality, CCA can be used for identifying the importance of risk factors for breast cancer recurrence. This technique can result in a model ready for further processing by data mining methods through reducing the number of variables to important ones.

  • 250.
    Robinson, David
    et al.
    Section of Urology, Ryhov County Hospital, Jönköping, Sweden.
    Aus, Gunnar
    Department of Urology, Sahlgrens University Hospital, Goumlteborg, Sweden.
    Bak, Julia
    Linköpings universitet, Institutionen för molekylär och klinisk medicin. Linköpings universitet, Hälsouniversitetet.
    Gorecki, Tomasz
    County Hospital of Kalmar, Kalmar, Sweden.
    Herder, Anders
    Linköpings universitet, Institutionen för molekylär och klinisk medicin. Linköpings universitet, Hälsouniversitetet.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Varenhorst, Eberhard
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Urologiska kliniken i Östergötland.
    Long-term follow-up of conservatively managed incidental carcinoma of the prostate A multivariate analysis of prognostic factors2007Inngår i: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 41, nr 2, s. 103-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To evaluate the disease-specific mortality of conservatively managed incidental carcinoma of the prostate (T1a and T1b) in relation to prognostic factors.

    Material and methods: Since 1987 all patients with prostate cancer have been recorded and followed in the population-based Prostate Cancer Register of the South-East Healthcare Region in Sweden, which is covered by four departments of pathology. At two of these departments, tissue was obtained from 197 consecutive, previously untreated patients (aged <80 years) with incidental carcinoma who underwent transurethral resection of the prostate between 1987 and 1991. The amount of tumour, Gleason score and levels of Ki-67, p53, chromogranin A and serotonin were determined. Univariate analysis and multiple Cox regression hazard analysis were used for analysis.

    Results: During follow-up (mean 7.8 years; maximum 17.5 years), 158 patients (80%) had died, 33 of them of prostate cancer, corresponding to 17% of the entire cohort. Of 86 patients with Gleason score ≤5, three died of prostate cancer. Independent predictors of disease-specific mortality in multivariate analysis were category T1b prostate cancer, Gleason score >5 and high immunoreactivity of Ki-67.

    Conclusions: Elderly men with category T1a and/or Gleason score 4-5 prostate cancer have a favourable prognosis with conservative management. Immunohistochemical staining with Ki-67 may be of help in situations where further prognostic information is required.

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