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Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28–1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30–1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

© 2019, The Author(s). Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management. We thank Sue Healey for her contribution to CIMBA, in particular, for taking on the task of mutation classification with Olga Sinilnikova. BCFR Australia: We acknowledge Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR Ontario: We thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT (Baltic Familial Breast Ovarian Cancer Consortium Lithuanian section): We acknowledge Vilius Rudaitis and Laimonas Griˇskeviˇcius. CBCS (Copenhagen Breast Cancer Study, Rigshospitalet): We thank Bent Ejlertsen Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants. CNIO (Spanish National Cancer Centre): We thank Alicia Barroso, Rosario Alonso, and Guillermo Pita for their assistance. COH-CCGCRN (City of Hope Clinical Cancer Genomics Community Research Network): Patients were recruited for study from the City of Hope Clinical Cancer Genomics Community Research Network. CONSIT TEAM:We acknowledge Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy; Brunella Pilato of the Istituto Nazionale Tumori “Giovanni Paolo II”, Bari, Italy; and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. FCCC (Fox Chase Cancer Center):We thank Jo EllenWeaver and Betsy Bove, MD, for their technical support. GEMO (GeneticModifiers of cancer risk in BRCA1/2 mutation carriers):We pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet, initiated and coordinated GEMO until she died on June 30, 2014, and we thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unit´e Mixte de G´en´etique Constitutionnelle des Cancers Fr´equents, Hospices Civils de Lyon–Centre L´eon B´erard, Equipe G´en´etique du cancer du sein, Centre de Rechercheen Canc´erologie de Lyon: Olga Sinilnikova (deceased), Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, M´elanie L´eone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de G´en´etique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agn`es Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne-Marie Birot; Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud- Bataille; Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer; Centre L´eon B´erard, Lyon: Christine Lasset, Val´erie Bonadona, Sandrine Handallou; Centre François Baclesse, Caen: Agn`es Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera; Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger; CHUArnaud-de-Villeneuve,Montpellier: Isabelle Coupier, Pascal Pujol; Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Jo¨elle Fournier, Françoise R´evillion, Philippe Vennin (deceased), Claude Adenis; Centre Paul Strauss, Strasbourg: Dani`ele Muller, Jean-Pierre Fricker; Institut Bergoni´e, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy; Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel; CHU Grenoble: Dominique Leroux, H´el`ene Dreyfus, Christine Rebischung, Magalie Peysselon; CHU Dijon: Fanny Coron, Laurence Faivre; CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz; HˆotelDieu Centre Hospitalier, Chamb´ery: Sandra Fert Ferrer; Centre Antoine Lacassagne, Nice: Marc Fr´enay; CHU Limoges: Laurence V´enat-Bouvet; CHU Nantes: Capucine Delnatte; CHU Bretonneau, Tours: Isabelle Mortemousque; Groupe Hospitalier Piti´e-Salp´etri`ere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, MathildeWarcoin; CHU Vandoeuvre-les- Nancy: Johanna Sokolowska, Myriam Bronner; CHU Besançon: Marie-Agn`es Collonge-Rame, Alexandre Damette; Creighton University, Omaha, NE: Henry T. Lynch, Carrie L. Snyder. G-FAST (Ghent University Hospital): B.P. is a senior clinical investigator of FWO. We acknowledge the technical support of Ilse Coeneen Brecht Crombez. HCSC (Hospital Clinico San Carlos): We acknowledge Alicia Tosar and Paula Diaque for their technical assistance. HEBCS (Helsinki Breast Cancer Study):We thank Taru A. Muranen, Carl Blomqvist, MD, Kirsimari Aaltonen, MD, Irja Erkkil¨a, RN, and Virpi Palola, RN, for their help with the HEBCS data and samples. Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON consists of the following collaborating centers: Coordinating center: Netherlands Cancer Institute, Amsterdam: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center: J.M. Coll´ee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University NijmegenMedical Center: C.M. Kets, A.R.Mensenkamp; UniversityMedical Center Utrecht: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center: C.M. Aalfs, T.A.M. van Os; Vrije Universiteit Medical Center: J.J.P. Gille, Q.Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht: E.B. G´omez-Garcia, M.J. Blok; University Medical Center Groningen: J.C. Oosterwijk, A.H. van der Hout, M.J.Mourits, G.H. de Bock; The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J. Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HUNBOCS (Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary):We thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. HVH (University Hospital Vall d’Hebron): We thank the Cellex Foundation for providing research facilities and equipment. ICO (Institut Catal`a d’Oncologia): We thank the ICO Hereditary Cancer Program team led by Gabriel Capella, MD. INHERIT (INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility):We thank Martine Dumont, MD, Martine Tranchant and St´ephane Dubois for QC, sample management and skillful assistance. J.S. is Chair holder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS and Oncoarray (BCAC and CIMBA). IPOBCS (Portuguese Oncology Institute-Porto jco.org © 2017 by American Society of Clinical Oncology Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers Downloaded from ascopubs.org by CNIO-FUND on September 27, 2019 from 193.147.150.201 Copyright © 2019 American Society of Clinical Oncology. All rights reserved. Breast Cancer Study): We thank Catarina Santos, MD, for her skillful contribution to the study. kConFab (Kathleen Cuningham Consortium for Research into Familial Breast Cancer): We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study for their contributions to this resource, and the many families who contribute to kConFab.Memorial Sloan Kettering Cancer Center:We acknowledge Lauren Jacobs, MD. OCGN (Ontario Cancer Genetics Network): We thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSUCCG (The Ohio State University Comprehensive Cancer Center): Kevin Sweet, Caroline Craven, Julia Cooper, Leigha Senter, and Michelle O’Conor were instrumental in accrual of study participants, ascertainment of medical records, and database management. SEABASS (South East Asian Breast Cancer Association Study): We thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection, and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively. SWE-BRCA (Swedish Breast Cancer Study): Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: A° ke Borg, H°akan Olsson, Helena Jernstr¨om, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna O¨ fverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna vonWachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Ume°a University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstr¨om Pigg, Richard Rosenquist; from Link¨oping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. University of Chicago: O.I.O. is an ACS Clinical Research Professor. We thank Cecilia Zvocec, Qun Niu, physicians, genetic counsellors, research nurses, and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. VFCTG (Victorian Familial Cancer Trials Group):We acknowledge Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group.We thank Sarah Sawyer and Rebecca Driessen for assembling these data and Ella Thompson for performing all DNA amplification. © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Sí

Contains fulltext : 172592.pdf (Publisher’s version ) (Open Access) A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 x 10(-20)), ER-negative BC (P=1.1 x 10(-13)), BRCA1-associated BC (P=7.7 x 10(-16)) and triple negative BC (P-diff=2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 x 10(-3)) and ABHD8 (P

PMCID: PMC3319317.-- et al., [Background]: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). [Methods]: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. [Results]: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). [Conclusions]: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. [Impact]: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers., This research was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341), and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. This work was also supported by Cancer Research UK (CR-UK) grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175). Support was also provided by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and by the Canadian Breast Cancer Research Alliance-grant #019511., A.C. Antoniou is a CR-UK Senior Cancer Research Fellow. D.F. Easton is CR-UK Principal Research Fellow. G. Chenevix-Trench6 is a NHMRC Senior Principal Research Fellow. BFBOCC was supported by the Research Council of Lithuania grant LIG-19/2010 to R. Janavicius. BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to E.J. van Rensburg. BCFR was supported by the National Cancer Institute, NIH under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (formerly the Northern California Cancer Center; U01 CA69417), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). CBCS was supported by The Neye Foundation. CNIO was partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, the Spanish Ministry of Science and Innovation (FIS PI08 1120), and the Basque Foundation for Health Innovation and Research (BIOEF): BIO07/CA/006. CONSIT TEAM was supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006 “Alleanza contro il Cancro” to L. Varesco and P. Radice, and “Progetto Tumori Femminili” to P. Radice), Ministero dell'Universita' e Ricerca (RBLAO3-BETH to P. Radice), Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors” to P. Radice), Associazione Italiana per la Ricerca sul Cancro (4017 to P. Pujol), and by funds from Italian citizens who allocated the 5 × 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”)., The DKFZ study was supported by funds from the DKFZ. EMBRACE was supported by CR-UK Grants C1287/A10118 and C1287/A11990. D.G. Evans and Fiona Lalloo were supported by an NIHR grant to the Biomedical Research Centre, Manchester, UK. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust were supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. R.A. Eeles, Elizabeth Bancroft, and Lucia D'Mello were supported by CR-UK Grant C5047/A8385. GC-HBOC was supported by a grant of the German Cancer Aid (grant 109076) and by the Centre of Molecular Medicine Cologne (CMMC). The GEMO study was supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association “Le cancer du sein, parlons-en!” Award. The Georgetown study was supported by the Familial Cancer Registry at Georgetown University (NIH/NCI grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C), and Swing Fore the Cure. GOG was supported through funding provided by both intramural (Clinical Genetics Branch, DCEG) and extramural (Community Oncology and Prevention Trials Program—COPTRG) NCI programs. K. Phillips is the Cancer Council Victoria, Colebatch Clinical Research Fellow. HEBCS was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HEBON study was supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, and the ZonMW grant 91109024. HUNBOCS was supported by the Hungarian Research Grant KTIA-OTKA CK-80745. ICO was supported by Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia; contract grant numbers ISCIIIRETIC RD06/0020/1051, PI10/01422, PI10/31488, and 2009SGR290. IHCC was supported by a Polish Foundation of Science award to K. Jaworska, a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. ILUH was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund., INHERIT was supported with J. Simard, Chairholder of the Canada Research Chair in Oncogenetics. IOVHBOCS was supported by Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), and “Ministero della Salute” (“Progetto Tumori Femminili and grant numbers RFPS 2006-5-341353, ACC2/R6.9”). kConFab was supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow-Up Study was funded by the NHMRC [145684, 288704, 454508]. A.-B. Skytte is supported by a NHMRC Senior Research Fellowship. A.K. Godwin was funded by U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund while at FCCC. The author acknowledges support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor. The McGill study was supported by the Jewish General Hospital Weekend to End Breast Cancer. M. Thomassen holds a Fonds de la Recherche en Santé du Québec clinician-scientist award. The MSKCC study was supported by the Starr Cancer Consortium, the Breast Cancer Research Foundation, the Norman and Carol Stone Cancer Research Initiative, the Kate and Robert Niehaus Clinical Cancer Research Initiative, the Lymphoma Foundation, and the Sabin Family Research Initiative. The NCI study was supported by the Intramural Research Program of the U.S. National Cancer Institute and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc. NNPIO was supported by the Russian Federation for Basic Research (grants 10-04-92601, 10-04-92110, 11-04-00227) and the Federal Agency for Science and Innovations (contract 16.512.11.2237)., OCGN was supported by Cancer Care Ontario and the U.S. National Cancer Institute, NIH under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators. OSU-CCG was supported by the Ohio State University Comprehensive Cancer Center. PBCS was supported by an Instituto Toscano Tumori grant to M.A. Caligo. SEABASS was supported by CARIF and University Malaya. The UCSF study was supported by the Helen Diller Family Comprehensive Cancer Center at UCSF, the Avon Foundation, and the Center for Translational and Policy Research in Personalized Medicine (TRANSPERS), NIH/NCI P01 CA130818-02A1. UKFOCR was supported by a project grant from CRUK to P.P.D. Pharoah. The UPENN study was supported Komen Foundation for the Cure to S.M. Domchek, the Breast Cancer Research Foundation to K.L. Nathanson, and NIH grants R01-CA083855 and R01-CA102776 to T.R. Rebbeck. WCRI was supported by the American Cancer Society Clinical Research Professorship #SIOP-06-258-06-COUN.

International audience; Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).

Contains fulltext : 110606.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

Contains fulltext : 97737.pdf (Publisher’s version ) (Open Access) ABSTRACT: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.