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Askmalm Stenmark, Marie
Alternative names
Publications (10 of 31) Show all publications
Couch, F. J., Kuchenbaecker, K. B., Michailidou, K., Mendoza-Fandino, G. A., Nord, S., Lilyquist, J., . . . Antoniou, A. C. (2016). Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. Nature Communications, 7(11375), 1-13
Open this publication in new window or tab >>Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
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2016 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 7, no 11375, p. 1-13Article in journal (Refereed) Published
Abstract [en]

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-128757 (URN)10.1038/ncomms11375 (DOI)000374894400001 ()27117709 (PubMedID)
Note

Funding Agencies|European Community Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A10710, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C12292/A11174]; National Institutes of Health [CA116201, CA128978, CA176785, CA192393]; National Institutes of Health, Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; National Institutes of Health, GAME-ON initiative; Canadian Institutes of Health Research (CIHR); Breast Cancer Res. Foundation; Ovarian Cancer Research Fund; Department of Defence [W81XWH-10-1-0341]; Florida Breast Cancer Foundation

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2023-03-28
Johansson, J., Sahin, C., Pestoff, R., Ignatova, S., Forsberg, P., Edsjö, A., . . . Stenmark Askmalm, M. (2015). A Novel SMAD4 Mutation Causing Severe Juvenile Polyposis Syndrome with Protein Losing Enteropathy, Immunodeficiency, and Hereditary Haemorrhagic Telangiectasia.. Case Reports in Gastrointestinal Medicine, 2015, 1-5, Article ID 140616.
Open this publication in new window or tab >>A Novel SMAD4 Mutation Causing Severe Juvenile Polyposis Syndrome with Protein Losing Enteropathy, Immunodeficiency, and Hereditary Haemorrhagic Telangiectasia.
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2015 (English)In: Case Reports in Gastrointestinal Medicine, ISSN 2090-6528, E-ISSN 2090-6536, Vol. 2015, p. 1-5, article id 140616Article in journal (Refereed) Published
Abstract [en]

Juvenile polyposis syndrome (JPS) is a rare genetic disorder characterized by juvenile polyps of the gastrointestinal tract. We present a new pathogenic mutation of the SMAD4 gene and illustrate the need for a multidisciplinary health care approach to facilitate the correct diagnosis. The patient, a 47-year-old Caucasian woman, was diagnosed with anaemia at the age of 12. During the following 30 years, she developed numerous gastrointestinal polyps. The patient underwent several operations, and suffered chronic abdominal pain, malnutrition, and multiple infections. Screening of the SMAD4 gene revealed a novel, disease-causing mutation. In 2012, the patient suffered hypoalbuminemia and a large polyp in the small bowel was found. Gamma globulin was given but the patient responded with fever and influenza-like symptoms and refused more treatment. The patient underwent surgery in 2014 and made an uneventful recovery. At follow-up two months later albumin was 38 g/L and IgG was 6.9 g/L. Accurate diagnosis is essential for medical care. For patients with complex symptomatology, often with rare diseases, this is best provided by multidisciplinary teams including representatives from clinical genetics. Patients with a SMAD4 mutation should be followed up both for JPS and haemorrhagic hereditary telangiectasia and may develop protein loosing enteropathy and immunodeficiency.
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-115933 (URN)10.1155/2015/140616 (DOI)25705527 (PubMedID)
Available from: 2015-03-24 Created: 2015-03-24 Last updated: 2025-02-11
Blanco, I., Kuchenbaecker, K., Cuadras, D., Wang, X., Barrowdale, D., Ruiz de Garibay, G., . . . Angel Pujana, M. (2015). Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers. PLOS ONE, 10(4), Article ID e0120020.
Open this publication in new window or tab >>Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers
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2015 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 4, article id e0120020Article in journal (Refereed) Published
Abstract [en]

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values greater than 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-117653 (URN)10.1371/journal.pone.0120020 (DOI)000352135600019 ()25830658 (PubMedID)
Note

Funding Agencies|National Cancer Institute [UM1 CA164920]; Lithuania (BFBOCC-LT): Research Council of Lithuania grant [LIG-07/2012]; Hereditary Cancer Association (Paveldimo vezio asociacija); LSC grant [10.0010.08]; ESF [2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016]; Liepajas municipal council; Cancer Association of South Africa (CANSA); Morris and Horowitz Familes Endowed Professorship; NEYE Foundation; Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA); COH-CCGCRN: City of Hope Clinical Cancer Genetics Community Network from the National Cancer Institute and the Office of the Director, National Institutes of Health; Hereditary Cancer Research Registry from the National Cancer Institute and the Office of the Director, National Institutes of Health [RC4CA153828]; Fondazione IRCCS Istituto Nazionale Tumori; Cancer Research-United Kingdom grant [C12292/A11174, C1287/ A10118]; NHMRC Program Grant; DKFZ; European Union (European Social Fund-ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF)-Research Funding Program of the General Secretariat for Research and Technology: ARISTEIA; European Social Fund; Cancer Research United Kingdom Grants [C1287/A10118, C1287/A11990]; National Institute of Health Research (NIHR) grant; NIHR grant; Royal Marsden NHS Foundation Trust; Cancer Research United Kingdom Grant [C5047/A8385]; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; AKG [5U01CA113916, R01CA140323]; German Cancer Aid [109076]; Center for Molecular Medicine Cologne (CMMC); Ligue National Contre le Cancer; Association "Le cancer du sein, parlonsen!" Award; Canadian Institutes of Health Research; Fund for Scientific Research Flanders (FWO); National Cancer Institute grant [CA 27469]; GOG Statistical and Data Center [CA 37517]; GOGs Cancer Prevention and Control Committee [CA 101165]; Intramural Research Program, NCI; ISCIII (Spain) [RD12/00369/0006, 12/00539]; European Regional Development FEDER funds; Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; Dutch Cancer Society grant [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon grant [110005]; BBMRI grant [NWO 184.021.007/CP46]; Hungarian Research Grant [KTIA-OTKA CK-80745]; Norwegian EEA Financial Mechanism [HU0115/NA/2008-3/OP-9]; Spanish Ministry of Health ISCIII FIS [PI10/01422, PI12/01528, PI13/00285]; RTICC [RD12/0036/0008]; Ramon Areces (XV) Foundation; Eugenio Rodriguez Pascual Foundation; Roses Contra el Cancer Foundation; Spanish Association Against Cancer (AECC); AGAUR Generalitat de Catalunya [2009-SGR290, 2009-SGR293]; Polish Foundation of Science; Icelandic Association "Walking for Breast Cancer Research"; Nordic Cancer Union; Landspitali University Hospital Research Fund; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade-grant [PSR-SIIRI-701]; Ministero dellIstruzione, dellUniversita e della Ricerca and Ministero della Salute; Liga Portuguesa Contra o Cancro; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Foundation of Western Australia; Cancer Councils of Tasmania; National Institutes of Health grant [CA128978]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; United States Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; Breast Cancer Research Foundation; Jewish General Hospital Weekend; Quebec Ministry of Economic Development, Innovation and Export Trade; Cancer Councils of South Australia; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; MH CZ-DRO (MMCI) [00209805]; Niehaus Family Genetics Research Fund; STARR Cancer Consortium Grant; NAROD [1R01 CA149429-01]; NCI Intramural Research Program, National Institutes of Health [NO2-CP-11019-50, N02-CP-65504]; Westat, Inc, Rockville, Maryland; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF), New York; Russian Federation for Basic Research [11-04-00227, 12-04-00928, 12-04-01490]; Federal Agency for Science and Innovations, Russia [02.740.11.0780]; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and grant from the National Cancer Institute [UM1 CA164920]; Breast Cancer Family Registry (BCFR); United States Government or the BCFR; Ohio State University Comprehensive Cancer Center; Isreal cancer association; Israeli Inherited breast cancer consortium; Swedish Cancer Society; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Womens Cancer Research Alliance; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Rooney Family Foundation; Susan G. Komen Foundation for the cure, Basser Research Center; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; SAF2010-20493; [PBZ_KBN_122/P05/2004]

Available from: 2015-05-12 Created: 2015-05-06 Last updated: 2021-06-14
Peterlongo, P., Chang-Claude, J., Moysich, K. B., Rudolph, A., Schmutzler, R. K., Simard, J., . . . Friedman, E. (2015). Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. Cancer Epidemiology, Biomarkers and Prevention, 24(1), 308-316
Open this publication in new window or tab >>Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
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2015 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 1, p. 308-316Article in journal (Refereed) Published
Abstract [en]

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
Place, publisher, year, edition, pages
American Association for Cancer Research, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-114432 (URN)10.1158/1055-9965.EPI-14-0532 (DOI)000348030700038 ()25336561 (PubMedID)
Note

Funding Agencies|European Community (COGS) [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/ A15007, C5047/A10692, C1287/A16563, C1287/A17523, C5047/A8385]; NIH [CA128978, R01-CA102776, R01CA083855]; Post-Cancer GWAS initiative [1U19CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute [UM1 CA164920, RC4CA153828]; Research Council of Lithuania [LIG-07/2012]; Cancer Association of South Africa (CANSA); Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI12/00070]; Mutua Madrilena Foundation (FMMA); City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry (COH-CCGCRN); Fondazione IRCCS Istituto Nazionale dei Tumori; DKFZ; NIHR grant to the Biomedical Research Centre, Manchester; NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research; Royal Marsden NHS Foundation Trust; German Cancer Aid [109078]; Center for Molecular Medicine Cologne (CMMC); Ligue National Contre le Cancer; Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Helsinki University Central Hospital Research Fund, Academy of Finland [266528]; Finnish Cancer Society and the Sigrid Juselius Foundation; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon [110005]; BBMRI [NWO 184.021.007/CP46]; Hungarian Research Grants [KTIA OTKA CK-80745, OTKA K-112228]; Asociacion Espanola Contra el Cancer; Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, 2009SGR290]; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital Research Fund; Ministero della Salute; Istituto Oncologico Veneto; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; David and Margaret T. Grohne Family Foundation; Ting Tsung and Wei Fong Chao Foundation; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Ohio State University Comprehensive Cancer Center; Swedish Cancer Society; Womens Cancer Program (WCP) at the Samuel Oschin Comprehensive Cancer Institute - American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; NEYE Foundation; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research Technology:; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank [CA 27469]; GOG Statistical and Data Center [CA 37517]; NCIs Community Clinical Oncology Program (CCOP) grant [CA 101165]; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade - grant [PSR-SIIRI-701]; Israel Cancer Association; Israeli Inherited Breast Cancer Consortium; Susan G. Komen Foundation; Basser Research Center; ISCIII [RD12/00369/0006]; European Regional Development funds, Spain; Morris and Horowitz Families Endowed Professorship; Chancellors Distinguished Chair in Biomedical Sciences Professorship; Intramural Research Program of the US National Cancer Institute; NIH; Westat, Inc; [PBZ_KBN_122/P05/2004]; [1R01 CA149429-01]; [5U01CA113916]; [R01CA140323]; [NO2-CP-11019- 50]; [N02-CP-65504]

Available from: 2015-03-02 Created: 2015-02-20 Last updated: 2017-12-04
van Thuijl, H. F., Mazor, T., Johnson, B. E., Fouse, S. D., Aihara, K., Hong, C., . . . Costello, J. F. (2015). Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathologica, 129(4), 597-607
Open this publication in new window or tab >>Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
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2015 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, no 4, p. 597-607Article in journal (Refereed) Published
Abstract [en]

Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-na less than ve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.
Place, publisher, year, edition, pages
Springer Verlag (Germany), 2015
Keywords
Low-grade glioma; Temozolomide; Hypermutator; Mismatch repair; MGMT
National Category
Medical Genetics and Genomics
Identifiers
urn:nbn:se:liu:diva-117202 (URN)10.1007/s00401-015-1403-6 (DOI)000351517200008 ()25724300 (PubMedID)
Note

Funding Agencies|Accelerate Brain Cancer Cure; Grove Foundation; TDC Foundation; Anne and Jason Farber Foundation; UCSF Brain Tumor SPORE grant [NIH P50CA097257]; Dutch Cancer Society (KWF) [2009-4470]; foundation STOPHersentumoren; Edli foundation; LiU Cancer Research Network; Medical Research Council of Southeast Sweden; National Institute Of General Medical Sciences [T32GM008568]; National Institutes of Health [1T32CA15102201]; National Cancer Institute [R01CA169316]; Sontag Foundation; NCI RO1 [R01 CA163687]; Project for Development of Innovative Research on Cancer Therapeutics (P-Direct); Ministry of Education, Culture, Sports, Science and Technology of Japan [23134501, 24221011]

Available from: 2015-04-22 Created: 2015-04-21 Last updated: 2025-02-10
Kuchenbaecker, K. B., Ramus, S. J., Tyrer, J., Lee, A., Shen, H. C., Beesley, J., . . . Chenevix-Trench, G. (2015). Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nature Genetics, 47(2), 164-171
Open this publication in new window or tab >>Identification of six new susceptibility loci for invasive epithelial ovarian cancer
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2015 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 2, p. 164-171Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P less than 5 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
Place, publisher, year, edition, pages
Nature Publishing Group, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-114988 (URN)10.1038/ng.3185 (DOI)000348694700012 ()25581431 (PubMedID)
Note

Funding Agencies|European Commission Seventh Framework Programme [223175-HEALTH-F2-2009-223175]; Cancer Research UK [C12292/A11174, C1287/A10118]; Ovarian Cancer Research Fund; US National Cancer Institute GAME-ON Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113]; National Health and Medical Research Council of Australia Program Grant

Available from: 2015-03-09 Created: 2015-03-06 Last updated: 2017-12-04
Mosrati, M. A., Malmström, A., Lysiak, M., Krysztofiak, A., Hallbeck, M., Milos, P., . . . Söderkvist, P. (2015). TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma. Oncotarget, 6(18), 16663-16673
Open this publication in new window or tab >>TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma
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2015 (English)In: Oncotarget, E-ISSN 1949-2553, Vol. 6, no 18, p. 16663-16673Article in journal (Refereed) Published
Abstract [en]

Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNPs, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.
Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2015
Keywords
TERT polymorphism; TERT promoter mutations; IDH1 mutation; glioblastoma; IL-6
National Category
Medical Genetics and Genomics
Identifiers
urn:nbn:se:liu:diva-120882 (URN)10.18632/oncotarget.4389 (DOI)000359012000088 ()26143636 (PubMedID)
Note

Funding Agencies|Swedish Cancer foundation; Region Ostergotland research fund; FORSS

Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2025-02-10
Tzortzatos, G., Andersson, E., Soller, M., Stenmark Askmalm, M., Zagoras, T., Georgii-Hemming, P., . . . Mints, M. (2015). The gynecological surveillance of women with Lynch Syndrome in Sweden. Gynecologic Oncology, 138(3), 717-722
Open this publication in new window or tab >>The gynecological surveillance of women with Lynch Syndrome in Sweden
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2015 (English)In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 138, no 3, p. 717-722Article in journal (Refereed) Published
Abstract [en]

Objective. Women with Lynch syndrome (LS) have up to a 60% lifetime risk of endometrial cancer (EC) and up to a 24% risk of ovarian cancer (OC). Gynecological surveillance is recommended, but the benefit and how it should be performed remain unclear. The purpose of this study was to assess diagnostic modalities for gynecological screening of LS patients in Sweden and clinical outcome. Methods. A retrospective nationwide study of 170 women with molecularly confirmed LS. Data including gynecological LS screening history, biopsy results (if any), genetic records, number of screening visits, results from screening including transvaginal ultrasound (TVUS), endometrial biopsy (EB), blood test for tumor marker cancer antigen (CA) 125, prophylactic surgery including age at procedure, and setting from which screening data were obtained from medical records. Results. A total of 117 women were eligible for gynecological screening and of these, 86 patients attended screening visits. Of these, 41 underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy. Two patients (4.9%) were diagnosed with EC and two (4.9%) with precancerous lesions in conjunction with prophylactic surgery. Total incidence of gynecological cancer in the surveillance group (45 women) was 20% EC, 4% OC. Five patients had endometrial cancer or complex hyperplasia with atypia (n = 2) detected by endometrial biopsy. Four additional cases were detected due to interval bleeding. Both cases of ovarian cancer were detected by transvaginal ultrasound in patients with ovarian cysts under surveillance. The youngest woman with endometrial cancer was diagnosed at 35 years of age, before she was aware of her diagnosis of Lynch syndrome. Conclusions. Gynecological surveillance of women with Lynch syndrome may lead to earlier detection of precancerous lesions, which might have some impact on the morbidity from endometrial cancer although further studies are needed to prove this. Prophylactic hysterectomy with or without bilateral salpingo-oophorectomy reduces the cancer incidence. A practical approach to surveillance in Lynch syndrome women would be to offer annual surveillance beginning at age 30 years including probably both TVUS and EB in order to increase diagnostic yield with prospective data registry for follow-up studies. Prophylactic surgery could be performed at a suitable age after childbearing to obtain a balance between reducing the risk of cancer and minimizing long-term complications from premature menopause. (C) 2015 Elsevier Inc. All rights reserved.
Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2015
Keywords
Screening; Lynch syndrome; Endometrial cancer; Ovarian cancer
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121901 (URN)10.1016/j.ygyno.2015.07.016 (DOI)000361269300038 ()26177554 (PubMedID)
Note

Funding Agencies|Stockholm County Council [510 222]; Karolinska Institutet [510 222]; Swedish Labor Market Insurance

Available from: 2015-10-13 Created: 2015-10-12 Last updated: 2017-12-01
Söderlund Leifler, K., Asklid, A., Fornander, T. & Askmalm Stenmark, M. (2015). The RAD51 135G/C polymorphism is related to the effect of adjuvant therapy in early breast cancer. Journal of Cancer Research and Clinical Oncology, 141(5), 797-804
Open this publication in new window or tab >>The RAD51 135G/C polymorphism is related to the effect of adjuvant therapy in early breast cancer
2015 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 141, no 5, p. 797-804Article in journal (Refereed) Published
Abstract [en]

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

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

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

Conclusion: Breast cancer patients who were homozygous for the wildtype G allele had a significant benefit of radiotherapy. The results suggest that the RAD51 135G/C polymorphism predicts the effect of CMF chemotherapy in early breast cancer.
Place, publisher, year, edition, pages
Springer Publishing Company, 2015
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17954 (URN)10.1007/s00432-014-1859-0 (DOI)000352859700003 ()
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2017-12-13Bibliographically approved
Couch, F. J., Wang, X., McGuffog, L., Lee, A., Olswold, C., Kuchenbaecker, K. B., . . . Antoniou, A. C. (2013). Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk. PLOS Genetics, 9(3)
Open this publication in new window or tab >>Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
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2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 3Article in journal (Refereed) Published
Abstract [en]

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Place, publisher, year, edition, pages
Public Library of Science, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96489 (URN)10.1371/journal.pgen.1003212 (DOI)000316866700002 ()
Available from: 2013-08-23 Created: 2013-08-20 Last updated: 2017-12-06
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