Journal article

Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Vivek L Patel, Evan L Busch, Tara M Friebel, Angel Cronin, Goska Leslie, Lesley McGuffog, Julian Adlard, Simona Agata, Bjarni A Agnarsson, Munaza Ahmed, Kristiina Aittomaki, Elisa Alducci, Irene L Andrulis, Adalgeir Arason, Norbert Arnold, Grazia Artioli, Brita Arver, Bernd Auber, Jacopo Azzollini, Judith Balmana Show all

Cancer Research | AMER ASSOC CANCER RESEARCH | Published : 2020

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate c..

View full abstract

Grants

Awarded by National Cancer Institute


Awarded by Cancer Research UK


Awarded by European Community


Awarded by NIH


Awarded by Post-Cancer GWAS initiative - the GAME-ON initiative


Awarded by Department of Defense


Awarded by Canadian Institutes of Health Research (CIHR)


Awarded by Ministry of Economic Development, Innovation and Export Trade


Awarded by Research Council of Lithuania


Awarded by Spanish Ministry of Health - FEDER funds


Awarded by Spanish Ministry of Economy and Competitiveness (MINECO)


Awarded by NCI of the NIH


Awarded by Associazione Italiana Ricerca sul Cancro (AIRC)


Awarded by Italian Association for Cancer Research (AIRC)


Awarded by 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


Awarded by University of Kansas Cancer Center


Awarded by German Cancer Aid


Awarded by Free State of Saxony, Germany (LIFE -Leipzig Research Centre for Civilization Diseases)


Awarded by NIH/NCI grant


Awarded by Spanish Ministry of Health


Awarded by CIBERONC from ISCIII (Spain)


Awarded by Academy of Finland


Awarded by Dutch Cancer Society


Awarded by Netherlands Organization of Scientific Research grant


Awarded by Pink Ribbon grants


Awarded by BBMRI grant


Awarded by Transcan grant JTC 2012 Cancer


Awarded by Hungarian Research Grants


Awarded by "Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa"


Awarded by Autonomous Government of Catalonia


Awarded by Canadian Institutes of Health Research


Awarded by Ministry of Economic Development, Innovation and Export Trade grant


Awarded by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer


Awarded by Cancer Center Support Grant/Core Grant


Awarded by Westat, Inc, Rockville, MD


Awarded by Russian Federation for Basic Research


Awarded by NRG Oncology


Awarded by NRG SDMC grant


Awarded by NRG Administrative Office


Awarded by NRG Tissue Bank


Awarded by NRG Statistical and Data Center


Awarded by Italian Association of Cancer Research (AIRC)


Awarded by Tuscany Institute for Tumors (ITT) grant


Awarded by Ministry of Science, Technology and Innovation, Ministry of Higher Education


Awarded by American Cancer Society


Awarded by National Center for Advancing Translational Sciences (NCATS)


Awarded by Miguel Servet Progam



Funding Acknowledgements

The authors thank all the families and clinicians who contributed to the studies; Sue Healey, in particular taking on the task of PSV classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griskevicius; Drs. Janis Eglitis, Anna Krilova, and Aivars Stengrevics; Rosario Alonso and Guillermo Pita; Milena Mariani, Daniela Zaffaroni, Monica Barile, Irene Feroce, Riccardo Dolcetti, Laura Papi, Gabriele Lorenzo Capone, Viviana Gismondi, Daniela Furlan, Antonella Savarese, Aline Martayan, Brunella Pilato; the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. Ms. JoEllen Weaver and Dr. Betsy Bove; Marta Santamarina, Ana Blanco, Miguel Aguado, Uxia Esperon, and Belinda Rodriguez; IFE - Leipzig Research Centre for Civilization Diseases (Markus Loeffler, Joachim Thiery, Matthias Nuchter, Ronny Baber). We also thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan (Muhammad U. Rashid, Noor Muhammad, Sidra Gull, Seerat Bajwa, Faiz Ali Khan, Humaira Naeemi, Saima Faisal, Asif Loya, Mohammed Aasim Yusuf) and Bogota, Colombia (Ignacio Briceno, Fabian Gil). Genetic modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, who initiated and coordinated GEMO until she sadly passed away on the 30th June 2014. The team in Lyon (Olga M. Sinilnikova, Melanie Leone, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valerie Sornin) managed the GEMO samples until the biological resource center was transferred to Paris in December 2015. We want to thank all the GEMO collaborating groups for their contribution to this study: Coordinating Centre, Service de Genetique, Institut Curie, Paris, France: Oph~elie Bertrand, Anne-Marie Birot, Sandrine Caputo, Anas Dupre, Emmanuelle Fourme, Lisa Golmard, Claude Houdayer, Marine LeMentec, Virginie Moncoutier, Antoine de Pauw, Dominique Yen, and Inserm U900, Institut Curie, Paris, France: Fabienne Lesueur, Noura Mebirouk. Contributing centers: Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon -Centre Leon Bernard, Lyon, France: Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, Melanie Leone. Institut Gustave Roussy, Villejuif, France: Brigitte Bressac-dePaillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, ClermontFerrand, France: Yves-Jean Bignon, Nancy Uhrhammer. Centre Francois Baclesse, Caen, France: Pascaline Berthet, Laurent Castera, Dominique Vaur. Institut Paoli Calmettes, Marseille, France: Violaine Bourdon, Catherine Nogues, Tetsuro Noguchi, Cornel Popovici, Audrey Remenieras, Hagay Sobol. CHU Arnaud-de-Villeneuve, Montpellier, France: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille, France: Claude Adenis, Aurelie Dumont, Francoise Revillion. Centre Paul Strauss, Strasbourg, France: Daniele Muller. Institut Bergonie, Bordeaux, France: Emmanuelle Barouk-Simonet, Francoise Bonnet, Virginie Bubien, Michel Longy, Nicolas Sevenet, Institut Claudius Regaud, Toulouse, France: Laurence Gladieff, Rosine Guimbaud, Viviane Feillel, Christine Toulas.CHU Grenoble, France: Helene Dreyfus, Christine Dominique Leroux, Magalie Peysselon, Rebischung. CHU Dijon, France: Amandine Baurand, Geoffrey Bertolone, Fanny Coron, Caroline Jacquot, Sarab Lizard. CHU St-Etienne, France: Caroline Kientz, Marine Lebrun, Fabienne Prieur. Hotel Dieu Centre Hospitalier, Chambery, France: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice, France: Veronique Mari. CHU Limoges, France: Laurence Venat-Bouvet. CHU Nantes, France: Stephane Bezieau, Capucine Delnatte. CHU Bretonneau, Tours, and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Pitie-Salpetriere, Paris, France: Chrystelle Colas, Florence Coulet, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Sokolowska. CHU Besancon, France: Marie-Agnes Collonge-Rame, Alexandre Damette. CHU Poitiers, Centre Hospitalier d'Angouleme, and Centre Hospitalier de Niort, France: Hakima Lallaoui. CHU Nmes Caremeau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; Ilse Coene en Brecht Crombez; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Sofia Khan, Taru A. Muranen, Carl Blomqvist, Irja Erkkila, and Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N. S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collee, A. M. W. van den Ouweland, M.J. Hooning, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T. E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C. M. Kets; University Medical Center Utrecht, NL: M.G.E.M. Ausems, C.C. van der Pol; Amsterdam Medical Center, NL: C. M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumors, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Timea Pocza, Zoltan Matrai, Miklos Kasler, 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; the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d'Hebron, and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr.Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; 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 (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the NIH) for their contributions to this resource, and the many families who contribute to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, NIH, Bethesda, MD), Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich, and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic); Anne Lincoln, Lauren Jacobs; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O'Conor; Yip Cheng Har, Nur AishahMohd 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, Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively; the Meirav Comprehensive breast cancer center team at the Sheba Medical Center; Christina Selkirk; Hakan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Ofverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Gisela Barbany Bustinza; from Umea University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Maritta Hellstrom Pigg, Richard Rosenquist; from Linkoping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco, and Peggy Conrad and Salina Chan; Simon Gayther, Susan Ramus, Paul Pharoah, Carole Pye, Patricia Harrington, and Eva Wozniak; Geoffrey Lindeman, Marion Harris, Martin Delatycki, Sarah Sawyer, Rebecca Driessen, and Ella Thompson for performing all DNA amplification. E.L. Busch was supported by grants from the National Cancer Institute (5T32CA009001, P60-CA105641). The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. A.C. Antoniou is a Cancer ResearchUK Senior Cancer Research Fellow. G. Chenevix-Trench and A.B. Spurdle are NHMRC Research Fellows. iCOGS: the European Community's Seventh Framework Programme under grant agreement no.223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the NIH (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112 -the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSRSIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Quebec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (principal investigator: Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the NCI of the NIH under grant numbers R25CA112486 and RC4CA153828 (principal investigator: J. Weitzel) from the NCI and the Office of the Director, NIH. CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547 to P. Radice). Italian Association for Cancer Research (AIRC; grant no.16933 to L. Ottini). Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732 to P. Peterlongo). Associazione Italiana Ricerca sul Cancro (AIRC grant IG17734 to G. Giannini). DEMOKRITOS: European Union (European Social Fund -ESF) and 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: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. Fiona Lalloo is supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Elizabeth Bancroft is supported by Cancer Research UK Grant C5047/A8385FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: FISPI05/2275 and Mutua Madrilena Foundation (FMMA). GC-HBOC: German Cancer Aid (grant no 110837 to R.K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE -Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470).GEMO: Ligue Nationale Contre le Cancer; the Association " Le cancer du sein, parlons-en!" Award, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa). GEORGETOWN: the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. G-FAST: Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, NIH1R 03CA130065, and North California Cancer Center. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: The authors would like to particularly acknowledge the support of the Asociacion Espanola Contra el Cancer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economia y Competitividad) and "Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa" (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC), and the Institut Catala de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, and PERIS Project MedPerCan). IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program -grant #CRN87521 and the Ministry of Economic Development, Innovation and Export Trade grant #PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and "5 x 100000 Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New SouthWales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201),and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural Research Program of the NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP65504 withWestat, Inc, Rockville, MD.NICCC: Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Federation for Basic Research (grants 15-04-01744, 1654-00055, and 17-54-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM. C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer research Foundation. O.I. Olopade is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK. UPENN: Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS; grant no. UL1TR000124). S. Gutierrez-Enriquez is supported by the Miguel Servet Progam (CP10/00617).The authors thank all the families and clinicians who contributed to the studies; Sue Healey, in particular taking on the task of PSV classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griskevicius; Drs. Janis Eglitis, Anna Krilova, and Aivars Stengrevics; Rosario Alonso and Guillermo Pita; Milena Mariani, Daniela Zaffaroni, Monica Barile, Irene Feroce, Riccardo Dolcetti, Laura Papi, Gabriele Lorenzo Capone, Viviana Gismondi, Daniela Furlan, Antonella Savarese, Aline Martayan, Brunella Pilato; the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. Ms. JoEllen Weaver and Dr. Betsy Bove; Marta Santamarina, Ana Blanco, Miguel Aguado, Uxia Esperon, and Belinda Rodriguez; IFE -Leipzig Research Centre for Civilization Diseases (Markus Loeffler, Joachim Thiery, Matthias Nuchter, Ronny Baber). We also thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan (Muhammad U. Rashid, Noor Muhammad, Sidra Gull, Seerat Bajwa, Faiz Ali Khan, Humaira Naeemi, Saima Faisal, Asif Loya, Mohammed Aasim Yusuf) and Bogota, Colombia (Ignacio Briceno, Fabian Gil). Genetic modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M.Sinilnikova, who initiated and coordinated GEMO until she sadly passed away on the 30th June 2014. The team in Lyon (Olga M. Sinilnikova, Melanie Leone, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valerie Sornin) managed the GEMO samples until the biological resource center was transferred to Paris in December 2015. We want to thank all the GEMO collaborating groups for their contribution to this study: Coordinating Centre, Service de Genetique, Institut Curie, Paris, France: Oph~elie Bertrand, Anne-Marie Birot, Sandrine Caputo, Anas Dupre, Emmanuelle Fourme, Lisa Golmard, Claude Houdayer, Marine LeMentec, Virginie Moncoutier, Antoine de Pauw, Dominique Yen, and Inserm U900, Institut Curie, Paris, France: Fabienne Lesueur, Noura Mebirouk. Contributing centers: Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon -Centre Leon Bernard, Lyon, France: Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, Melanie Leone. Institut Gustave Roussy, Villejuif, France: Brigitte Bressac-dePaillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, ClermontFerrand, France: Yves-Jean Bignon, Nancy Uhrhammer. Centre Francois Baclesse, Caen, France: Pascaline Berthet, Laurent Castera, Dominique Vaur. Institut Paoli Calmettes, Marseille, France: Violaine Bourdon, Catherine Nogues, Tetsuro Noguchi, Cornel Popovici, Audrey Remenieras, Hagay Sobol. CHU Arnaud-de-Villeneuve, Montpellier, France: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille, France: Claude Adenis, Aurelie Dumont, Francoise Revillion. Centre Paul Strauss, Strasbourg, France: Daniele Muller. Institut Bergonie, Bordeaux, France: Emmanuelle Barouk-Simonet, Francoise Bonnet, Virginie Bubien, Michel Longy, Nicolas Sevenet, Institut Claudius Regaud, Toulouse, France: Laurence Gladieff, Rosine Guimbaud, Viviane Feillel, Christine Toulas. CHU Grenoble, France: Helene Dreyfus, Christine Dominique Leroux, Magalie Peysselon, Rebischung. CHU Dijon, France: Amandine Baurand, Geoffrey Bertolone, Fanny Coron, Caroline Jacquot, Sarab Lizard. CHU St-Etienne, France: Caroline Kientz, Marine Lebrun, Fabienne Prieur. Hotel Dieu Centre Hospitalier, Chambery, France: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice, France: Veronique Mari. CHU Limoges, France: Laurence V~enat-Bouvet. CHU Nantes, France: St~ephane Bezieau, Capucine Delnatte. CHU Bretonneau, Tours, and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Piti~e-Salp~etri~ere, Paris, France: Chrystelle Colas, Florence Coulet, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Sokolowska. CHU Besancon, France: Marie-Agnes Collonge-Rame, Alexandre Damette. CHU Poitiers, Centre Hospitalier d'Angouleme, and Centre Hospitalier de Niort, France: Hakima Lallaoui. CHU Nmes Caremeau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; Ilse Coene en Brecht Crombez; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Sofia Khan, Taru A. Muranen, Carl Blomqvist, Irja Erkkila, and Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N. S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Coll~ee, A. M. W. van den Ouweland, M.J. Hooning, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: J.T. Wijnen, R.A.E.M.Tollenaar, P. Devilee, T.C.T. E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C. M. Kets; University Medical Center Utrecht, NL: M.G.E.M. Ausems, C.C. van der Pol; Amsterdam Medical Center, NL: C. M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumors, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Timea Pocza, Zoltan Matrai, Miklos Kasler, 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; the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d'Hebron, and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; 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 (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the NIH) for their contributions to this resource, and the many families who contribute to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, NIH, Bethesda, MD), Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich, and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic); Anne Lincoln, Lauren Jacobs; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr.Mila Pinchev; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O'Conor; Yip Cheng Har, Nur AishahMohd 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, Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively; the Meirav Comprehensive breast cancer center team at the Sheba Medical Center; Christina Selkirk; Hakan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Ofverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Gisela Barbany Bustinza; from Umea University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Maritta Hellstrom Pigg, Richard Rosenquist; from Linkoping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco, and Peggy Conrad and Salina Chan; Simon Gayther, Susan Ramus, Paul Pharoah, Carole Pye, Patricia Harrington, and Eva Wozniak; Geoffrey Lindeman, Marion Harris, Martin Delatycki, Sarah Sawyer, Rebecca Driessen, and Ella Thompson for performing all DNA amplification. E.L. Busch was supported by grants from the National Cancer Institute (5T32CA009001, P60-CA105641). The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. A.C. Antoniou is a Cancer ResearchUK Senior Cancer Research Fellow. G. Chenevix-Trench and A.B. Spurdle are NHMRC Research Fellows. iCOGS: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the NIH (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112 -the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSRSIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Quebec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (principal investigator: Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER).COH-CCGCRN: Research reported in this publication was supported by the NCI of the NIH under grant numbers R25CA112486 and RC4CA153828 (principal investigator: J. Weitzel) from the NCI and the Office of the Director, NIH. CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547 to P. Radice). Italian Association for Cancer Research (AIRC; grant no.16933 to L. Ottini). Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732 to P. Peterlongo). Associazione Italiana Ricerca sul Cancro (AIRC grant IG17734 to G. Giannini). DEMOKRITOS: European Union (European Social Fund -ESF) and 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: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. Fiona Lalloo is supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Elizabeth Bancroft is supported by Cancer Research UK Grant C5047/A8385FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: FISPI05/2275 and Mutua Madrilena Foundation (FMMA). GC-HBOC: German Cancer Aid (grant no 110837 to R.K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE -Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association " Le cancer du sein, parlons-en!" Award, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa). GEORGETOWN: the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. G-FAST: Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, NIH1R 03CA130065, and North California Cancer Center. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228.ICO: The authors would like to particularly acknowledge the support of the Asociacion Espanola Contra el Cancer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economia y Competitividad) and "Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa" (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC), and the Institut Catal~a de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, and PERIS Project MedPerCan). IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program -grant #CRN87521 and the Ministry of Economic Development, Innovation and Export Trade grant #PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and "5 ~ 100000 Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New SouthWales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201),and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural Research Program of the NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP65504 withWestat, Inc, Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Federation for Basic Research (grants 15-04-01744, 1654-00055, and 17-54-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM. C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer research Foundation. O.I. Olopade is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK. UPENN: Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh.VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS; grant no. UL1TR000124). S. Gutierrez-Enriquez is supported by the Miguel Servet Progam (CP10/00617).