Discussion
DAE is a common phenomenon in human genes, which represents a new approach to identifying
cis-acting mechanisms of gene regulation. It offers a new avenue for the study of GWAS variants significantly associated with various diseases/traits. Indeed, the majority of GWAS hits localize outside known protein-coding regions [
11,
12], suggesting a regulatory role for these variants. In the present study, we have assessed the association between 320 SNPs associated with DAE and breast/ovarian cancer risk among
BRCA1 and
BRCA2 mutation carriers. Using this approach, we found evidence of association for a region at 11q22.3, with breast cancer risk in
BRCA1 mutation carriers. Analysis of imputed SNPs across a 185-kb region (±50 kb from the center of each of the three genotyped SNPs at this locus) revealed a set of five strongly correlated SNPs that were significantly associated with breast cancer risk. This region contains several genes including
ACAT1,
NPAT, and
ATM.
ACAT1 (
acetyl-
CoA
acetyl
transferase 1) encodes a mitochondrial enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA. Defects in this gene are associated with ketothiolase deficiency, an inborn error of isoleucine catabolism [
29].
NPAT (
nuclear
protein, co-
activator of histone
transcription) is required for progression through the G1 and S phases of the cell cycle, for S phase entry [
30], and for the activation of the transcription of histones H2A, H2B, H3, and H4 [
31].
NPAT germline mutations have been associated with Hodgkin lymphoma [
32]. Finally,
ATM (
ataxia
telangiectasia
mutated) encodes an important cell cycle checkpoint kinase that is required for cellular response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder [
33].
ATM is also an intermediate-risk breast cancer susceptibility gene, with rare heterozygous variants being associated with increased risk of developing the disease [
34]. Although several studies have assessed the role of the most common
ATM variants in breast cancer susceptibility, the results obtained are inconsistent [
35]. A recent study had identified an association between an
ATM haplotype and breast cancer risk in
BRCA1 mutation carriers with a false discovery rate-adjusted
p value of 0.029 for overall association of the haplotype [
36]. Four of the five SNPs making up the haplotype were almost perfectly correlated (
r
2 >0.9) with the three originally genotyped SNPs of the present study. These SNPs were, however, only moderately correlated (
r
2 >0.4) with the most significant risk SNPs (
p = 10
−6), identified later through imputation.
Although eQTL analysis has identified
cis-eQTL associations between several variants and
ACAT1,
ATM as well as other neighboring genes in both breast carcinoma and normal breast tissues, none of these associations involved the most significantly associated risk SNPs. Furthermore, the correlation between eQTLs and the most significant risk SNPs was weak. The lack of consistency between the eQTL results and the allelic imbalance data originally used for SNP selection in the design of the present study can probably be explained by the differences between the cell types used in these analyses. The list of allelic imbalance-associated SNPs was selected from studies performed in lymphoblastoid cell lines [
15], primary skin fibroblasts [
13,
16], and primary monocytes [
17], while eQTLs were analyzed in breast carcinoma and normal breast tissue. This tissue heterogeneity in the data sources used represents one of the limitations of this study, although no such data were available in mammary cells when this study was originally designed.
The identification of a region at 11q22.3 that is associated specifically with breast cancer risk in BRCA1 mutation carriers may explain why association studies performed using breast cancer cases from the general population have so far yielded conflicting results with regard to common variants at this locus. The majority of tumors arising in BRCA1 carriers show either low or absent ER expression, while the majority of BRCA2-associated tumors are ER positive, as in most sporadic cancers arising in the general population. Large-scale studies using only ER-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
Acknowledgments
Silje Nord was financed by a Carrier Grant from the Norwegian Regional Health authorities (Grant Number 2014061). BCFR-AU: Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR-NY: we wish to thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study. BCFR-ON: we wish to thank the members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT thank Vilius Rudaitis and Laimonas Griškevičius. BFBOCC-LV thank Drs. Janis Eglitis, Anna Krilova, and Aivars Stengrevics. BMBSA wish to thank the families who contribute to the BMBSA study. BRICOH: we wish to thank Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management. CBCS: we thank Bent Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants. CNIO: we thank Alicia Barroso, Rosario Alonso, and Guillermo Pita for their assistance. CONSIT TEAM: Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy; Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia, Milan; Maria Grazia Tibiletti of the Ospedale di Circolo-Università dell’Insubria, Varese, Italy; Liliana Varesco of the IRCCS AOU San Martino: IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Alessandra Viel of the CRO Aviano National Cancer Institute, Aviano, Italy; Gabriele Capone of the University of Florence, Florence, Italy; Laura Ottini and Giuseppe Giannini of the “Sapienza” University, Rome, Italy; Antonella Savarese and Aline Martayan of the Istituto Nazionale Tumori Regina Elena, Rome, Italy; Stefania Tommasi and Brunella Pilato of the Istituto Nazionale Tumori “Giovanni Paolo II,” Bari, Italy; and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. CORE: the CIMBA data management and analysis was funded through Cancer Research: UK Grant C12292/A11174. ACA is a Senior Cancer Research: UK Research Fellow. We wish to thank Sue Healey for her enormous contribution to CIMBA, in particular taking on the task of mutation classification with Olga Sinilnikova. EMBRACE: RE was supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: we thank Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support. GC-HBOC: we would like to thank LIFE: Leipzig Research Centre for Civilization Diseases (Markus Loeffler, Joachim Thiery, Matthias Nüchter, Ronny Baber). Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) Study: National Cancer Genetics Network «UNICANCER Genetic Group», France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014, and to thank all the GEMO Collaborating Groups for their contribution to this study. GEMO Collaborating Centers are as follows: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon: Centre Léon Bérard, and Equipe «Génétique du cancer du sein», Centre de Recherche en Cancérologie de Lyon: Olga Sinilnikova†, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Mélanie Léone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnès 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 Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona, Sandrine Handallou. Centre François Baclesse, Caen: Agnès Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger. CHU Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin†, Claude Adenis. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, 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, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon: Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU Limoges: Laurence Vénat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy: Johanna Sokolowska, Myriam Bronner. CHU Besançon: Marie-Agnès Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder. G-FAST: we wish to thank the technical support of Ilse Coene en Brecht Crombez. HCSC: we acknowledge the technical assistance of Alicia Tosar and Paula Diaque. HEBCS would like to thank Drs. Sofia Khan, Taru A. Muranen, Carl Blomqvist and RNs Irja Erkkilä and Virpi Palola for their help with the HEBCS data and samples. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating Center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, 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, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, 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, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gómez-Garcia, M.J. Blok; 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 Tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J. Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. The HEBON study was supported by 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 IKNL and PALGA for their help in part of the data collection. HRBCP: we wish to thank Hong Kong Sanatorium and Hospital for their continued support. HUNBOCS: we wish to thank the Hungarian Breast and Ovarian Cancer Study Group Members (Janos Papp, Tibor Vaszko, 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: we wish to thank the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron. Thanks to the Cellex Foundation for providing research facilities and equipment. ICO: we wish to thank the ICO Hereditary Cancer Program Team led by Dr. Gabriel Capella. INHERIT: we would like to thank Dr. Martine Dumont for sample management and skillful assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping Coordinating Group of iCOGS (BCAC and CIMBA). IPOBCS: we wish to thank Drs. Ana Peixoto, Catarina Santos, and Pedro Pinto for their skillful contribution to the study. KCONFAB: we wish to 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 [which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)] for their contributions to this resource, and the many families who contribute to kConFab. Modifier Study of Quantitative Effects on Disease (MODSQUAD) thank ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health,
Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, 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). MSKCC: Anne Lincoln, Lauren Jacobs. NICCC: we wish to thank 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. NRG Oncology: we thank the investigators of the Australia New Zealand NRG Oncology Group. OCGN: we wish to thank the members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSUCCG: Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O’Conor were instrumental in accrual of study participants, ascertainment of medical records, and database management. SEABASS: we would like to 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 their 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. The Malaysian Breast Cancer Genetic Study was funded by Research Grants from the Malaysian Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HIR/MOHE/06), and charitable funding from Cancer Research Initiatives Foundation. SMC Team wishes to acknowledge the assistance of the Meirav Comprehensive Breast Cancer Center Team at the Sheba Medical Center for their assistance in this study. SWE-BRCA: Swedish scientists participating as SWE-BRCA Collaborators are from Lund University and University Hospital: Åke Borg, Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; and from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. UCHICAGO: we wish to thank Cecilia Zvocec, Qun Niu, physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. UCLA: we thank Joyce Seldon MSGC and Lorna Kwan, MPH, for assembling the data for this study. UCSF: we would like to thank Dr. Robert Nussbaum and the following genetic counselors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco, and Peggy Conrad. And thanks to Ms. Salina Chan for her data management. UKFOCR: we thank Susan Ramus, Carole Pye, Patricia Harrington, and Eva Wozniak for their contributions toward the UKFOCR. VFCTG: Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling the data and Ella Thompson for performing all DNA amplification.
Funding
Funding for the iCOGS infrastructure came from 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 National Institutes of Health (CA128978) and Post-cancer GWAS Initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112: the GAME-ON Initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCFR: this work was supported by Grant UM1 CA164920 from the National Cancer Institute. BFBOCC was supported by Lithuania (BFBOCC-LT): Research Council of Lithuania Grant SEN-18/2015. BIDMC was supported by the Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by Grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. BRICOH: SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. CNIO: this work was partially supported by Spanish Association Against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA), and SAF2010-20493. COH-CCGCRN: patients were recruited for this study from the City of Hope Clinical Cancer Genomics Community Research Network, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONSIT Team: Associazione Italiana Ricerca sul Cancro (AIRC) to P. Peterlongo (IG 2012 Id.12821) and P. Radice (IG 2014 Id.15547). Funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional Strategic Projects ‘5x1000’) to S. Manoukian. FiorGen Foundation for Pharmacogenomics to L. Papi. CORE: the CIMBA Data Management and Data Analysis were supported by Cancer Research: UK Grants C12292/A20861, C12292/A11174. ACA is a Cancer Research-UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. J. Lecarpentier has been financially supported by the Fondation ARC (FONDATION ARC, 9 rue Guy Môquet 94803 Villejuif: France), Grant Number SAE20131200623. This work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, Innovation et Exportation du Québec through Genome Québec, and The Quebec Breast Cancer Foundation. This work was also supported by the Ministère de l’Économie, Innovation et Exportation du Québec: Grant No. PSR-SIIRI-701. DEMOKRITOS: this research has been co-financed by the 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 and Technology: SYN11_10_19 NBCA. Investing in Knowledge Society through the European Social Fund. The DKFZ Study was supported by the DKFZ. EMBRACE was supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo were 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 were supported by an NIHR Grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft were supported by Cancer Research UK Grant C5047/A8385. Ros Eeles was also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: the authors acknowledge the support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) was supported by the German Cancer Aid (Grant No. 110837, Rita K. Schmutzler). This work was supported by 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: the study was supported by the 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: CI received support from 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 was supported by a Grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER Funds. The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON Study was supported by the Dutch Cancer Society Grants NKI1998-1854, NKI2004-3088, and 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 their help in part of the data collection. HRBCP was supported by the Hong Kong Sanatorium and Hospital, Dr. Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health 1R 03CA130065, and North California Cancer Center. Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: Contract Grant Sponsor: 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, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, and 2014SGR364. The IHCC was supported by Grant PBZ_KBN_122/P05/2004. The ILUH Group was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INHERIT: this work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (Grant GPH-129344), the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec, and the Quebec Breast Cancer Foundation. IOVHBOCS was supported by Ministero della Salute and “5x1000” Istituto Oncologico Veneto Grant. IPOBCS: this study was in part supported by Liga Portuguesa Contra o Cancro. kConFab was supported by a Grant from 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 South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. KOHBRA was supported by a Grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). MAYO was supported by 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. MODSQUAD was supported by MH CZ: DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague Project UNCE204024 (MZ). MSKCC was supported by Grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NAROD: 1R01 CA149429-01. NCI: the research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by Support Services Contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD. NICCC was supported by Clalit Health Services in Israel. Some of its activities were supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: this work has been supported by the Russian Federation for Basic Research (Grants 15-04-01744 and 16-54-00055). NRG Oncology: this study was supported by NRG Oncology Operations Grant Number U10 CA180868 as well as NRG SDMC Grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469), and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai, and Savage were supported by Funding from the Intramural Research Program, NCI. OSUCCG was supported by the Ohio State University Comprehensive Cancer Center. PBCS: this work was supported by the 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. The SMC Team was in part sponsored by a Grant from the Israeli Cancer Association to the Israeli Consortium of Hereditary Breast Cancer. SWE-BRCA Collaborators were supported by the Swedish Cancer Society. UCHICAGO was supported by 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. OIO 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 was supported by a Project Grant from CRUK to Paul Pharoah. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Research Center for BRCA. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr. Karlan was funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124.