© The Author 2010. Published by Oxford University Press.
Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers
Affiliation of authors: Department of Gynaecological Oncology, UCL EGA Institute for Women's Health, University College London, London, UK (SJR, SAG); Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (CK, LM, SP, MC, CO, DF, ACA); Cancer Research United Kingdom Department of Oncology and Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK (PDPP); Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, and Equipe labellisée LIGUE 2008, UMR5201 CNRS, Centre Léon Bérard, Université de Lyon, Lyon, France (OMS); Queensland Institute of Medical Research, Brisbane, Queensland, Australia (JBee, XC, SHe, ABS, HH, GC-T); Department of Laboratory Medicine and Pathology (FJC, XW) and Department of Health Sciences Research (ZF), Mayo Clinic, Rochester, MN; Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), and IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy (PP, PR); Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy (SMa, BP, DZ, GR); Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy (MB); Division of Experimental Oncology 1, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano (PN), Italy (AV); Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy (AA); Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy (LO); Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy (LP); Department of Epidemiology and Prevention, IRCCS Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa, Italy (VG); Cogentech, Consortium for Genomics Technology, Milan, Italy (FC); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (MHG, PLM); Ontario Cancer Genetics Network, Cancer Care Ontario and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (ILA); Ontario Cancer Genetics Network, Cancer Care Ontario, Toronto, ON, Canada (GG); Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (HO); Clinical Genetics, Odense University Hospital, Odense, Denmark (MT, TAK, A-MG); Clinical Genetics, Rigshospital Copenhagen, Denmark (A-MG); Clinical Genetics, Vejle Hospital, Vejle, Denmark (DC); Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark (UBJ); Section of Genetic Oncology, Department of Oncology, University Hospital of Pisa, Pisa, Italy (MAC); Department of Oncology (HO, AB) and Department of Clinical Genetics (UK), Lund University, Lund, Sweden; Department of Clinical Genetics (AL) and Department of Oncology (BA), Karolinska University Hospital, Stockholm, Sweden; Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden (PK); Department of Oncology, Linköping University Hospital, Linköping, Sweden (MSA); Department of Population Sciences, the Beckman Research Institute of the City of Hope, Duarte, CA (SLN, YCD), Department of Medicine and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA (KLN, SMD); International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland ( AJ, JL, TH, TB, JGron, BG, CCy, TD); Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain (AO); Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain (MD); Molecular Genetics Laboratory (Department of Biochemistry), Cruces Hospital Barakaldo, Bizkaia, Spain (M-IT); Human Genetics Group and Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain (JB); Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (UH); Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands (MAR); Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, the Netherlands (SV); Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands (MAT-L); Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands (MPV, CJA); DNA Diagnostics, Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands (DB); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (TAvO); Department of Clinical Genetics, University Hospital Maastricht, Maastricht, the Netherlands (MJB); Department of Clinical Genetics, VU Medical Center, Amsterdam, the Netherlands (HEJM-H); Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK (AMD); Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK (DGE); Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, UK (RE); Clinical Genetics, Guy's and St Thomas’ NHS Foundation Trust, London, UK (GP); West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK (TCo); Clinical Genetics Department, St George's Hospital, University of London, London, UK (SH); Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK (CB); Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK (PJM ); South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK (MP); Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire (MJK); All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK (MTR); North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK (LES);Clinical Genetics Department, St Michael's Hospital, Bristol, UK (AD); North of Scotland Regional Genetics Service, NHS Grampian and University of Aberdeen, Aberdeen, UK (HG); Women's Cancer Program, Departrment of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA ( AKG, MBD); INSERM U509, Service de Génétique Oncologique, Institut Curie, Université Paris-Descartes, Paris, France (DS-L, VM, LC); Equipe labellisée LIGUE 2008, UMR5201 CNRS, Centre Léon Bérard, Université de Lyon, Lyon, France (SM, LB); CNRS UMR5558, Université Lyon 1, and Unité de Prévention et d’Epidémiologie Génétique, Centre Léon Bérard, Lyon, France (VB); Department of Genetics, Centre Hospitalier Universitaire de Grenoble, and Institut Albert Bonniot, Université de Grenoble, Grenoble, France (DL); Centre de Génétique, Centre Hospitalier Universitaire de Dijon, and Centre de Lutte Contre le Cancer Georges François Leclerc, Dijon, France (LF); INSERM U735, Centre René Huguenin, Saint-Cloud, France (RL); Epidémiologie Clinique, Oncogénétique, Centre René Huguenin, Saint-Cloud, France (CN); Département d’Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France (Y-JB); Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France (FP); Service de Génétique-Histologie-Biologie du Développement et de la Reproduction, Centre Hospitalier Universitaire de Besançon, Besançon, France (M-ACR); Department of Medical Oncology, Centre Hospitalier Universitaire Dupuytren, Limoges, France (LV-B); Laboratoire de Génétique Chromosomique, Hôtel Dieu Centre Hospitalier, Chambéry, France (SFF); Women's Cancers Program, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA (AMi); Huntsman Cancer Institute, University of Utah Health Sciences Centre, Salt Lake City, UT (SSB); Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, The University of Melbourne, Melbourne, Australia (JLH); Cancer Prevention Institute of California (formerly the Northern California Cancer Center), Fremont and Stanford University School of Medicine, Stanford, CA (EMJ); Department of Epidemiology, Joseph L. Mailman School of Public Health, Columbia University, NY (MBT); Department of Dermatology, University of Utah, Utah (DGo); Department of Clinical Biochemistry (TvOH, LJ) and Department of Oncology (BE), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Pathology, University Hospital and University of Iceland School of Medicine, Reykjavik, Iceland (BAA); Clinical Genetics Service, Department of Medicine, Memorial Sloan- Kettering Cancer Center, New York, NY (KO, TK, JV, AVCD-C, JAP); Istituto Oncologico Veneto—IRCCS, Immunology and Molecular Oncology Unit, Padua, Italy (MM, CC); N.N. Petrov Institute of Oncology, St-Petersburg, Russia (ENI); Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology and Transfusion Medicine Center, Vilnius, Lithuania (RJ); Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Spain (IB, CL); Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY (KBM); Women's Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, CA (BYK, JG); University of California, San Francisco (UCSF) Cancer Risk Program and Department of Medicine, Department of Epidemiology, and Department of Biostatistics, UCSF, San Francisco, CA (MSB); Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University hospital of Cologne, Germany (RS, BW); Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Germany (AM); Department of Gynaecology and Obstetrics, Ludwig- Maximillians University Munich, Germany (IR); Institute of Human Genetics, University of Regensburg, Regensburg, Germany (BF); Institute of Human Genetics, Department of Human Genetics, Laboratory of Molecular Genetics, University of Heidelberg, Heidelberg, Germany (CS); Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Germany (NA); Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany (HD); Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany (RV-M); Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Germany (KK); Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Germany (DN); Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany (DG); Molecular Oncology Laboratory, Hospital San Carlos, Madrid, Spain (TC, MdlH); Helsinki University Central Hospital, Department of Obstetrics and Gynecology, Helsinki, Finland (HN); Helsinki University Central Hospital, Department of Clinical Genetics, Helsinki, Finland (KA); Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec, Canada (JS, PS); Cancer Research United Kingdom Genetic Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom (DFE)
Received May 18, 2010; Revised October 14, 2010; Accepted November 4, 2010.
The CIMBA data management and data analysis was supported by Cancer Research UK grants (to D.F.E. and A.C.A.). G.C.-T. founded CIMBA to provide the infrastructure to study genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers.
Breast Cancer Family Registry (BCFR): Supported by the National Cancer Institute (NCI), National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators (PIs), including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Northern California Cancer Center (U01 CA69417), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). The content of this article does not necessarily reflect the views or policies of the NCI or any of the collaborating centers in the BCFR nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.
Copenhagen Breast Cancer Study (CBCS): Supported by the Neye Foundation.
Spanish National Cancer Center (CNIO) and the Spanish Consortium: Partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, and the Spanish Ministry of Science and Innovation (FIS PI08 1120). Funded in part by the Basque Foundation for Health Innovation and Research (BIOEF) (BIO07/CA/006).
CONsorzio Studi Italiani Tumori Ereditari Alla Mammella (CONSIT TEAM): Supported by grants from Associazione Italiana per la Ricerca sul Cancro (4017) and by 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 “5×1000”) to P.P. Supported by grants from Ministero della Salute (“Progetto Tevere”—Linea 1 RC D/08/02B—“Progetto Tumori Femminili”—F/08/0PZ—Linea1 RC CORR/08) to S.M. Supported by grants from Associazione Italiana per la Ricerca sul Cancro (8713) to L.O. Supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006, “Alleanza contro il Cancro” and Integrated Program N.5) to V.G. Supported by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors”), Ministero della Salute (RFPS-2006-3-340203, Extraordinary National Cancer Program 2006 “Alleanza contro il Cancro,” and “Progetto Tumori Femminili”) and Ministero dell’Universita’ e Ricerca (RBLAO3-BETH) to P.R.
Deutsches Krebsforschungszentrum (DKFZ) study: Supported by the DKFZ.
Epidemiological study of BRCA1 and BRCA2 mutation carriers (EMBRACE): Cancer Research UK grants (C1287/A10118 and C1287/A8874 to D.F.E., S.P., M.C., D.F., and C.O., and C8197/A10123 and C8197/A10865 to A.M.D.). National Institute for Health Research grant to the Biomedical Research Centre, Manchester (D.G.E.). The Investigators at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust are supported by a National Institute of Health Research grant to the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. Cancer Research UK grant (C5047/A8385 to R.E., E.B., and L.D’M.).
Fox Chase Cancer Center (FCCC): National Institutes of Health (P50 CA83638, U01 CA69631, and 5U01 CA113916 to A.K.G.); Eileen Stein Jacoby Fund.
The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): German Cancer Aid (107054).
Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): Cancer Genetics Network “Groupe Génétique et Cancer,” Fédération Nationale des Centres de Lutte Contre le Cancer, France, is supported by the Ligue National Contre le Cancer; Association for International Cancer Research grant (AICR-07-0454); Association “Le cancer du sein, parlons-en!” Award.
The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): Dutch Cancer Society (NKI 1998-1854, NKI 2004-3088 and NKI 2007-3756).
Hospital Clinico San Carlos: National Institute of Health Carlos III (RTICC 06/0020/0021, FIS 070359, and FIS 0900850).
Helsinki Breast Cancer Study (HEBCS): Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation.
International Hereditary Cancer Center: State Committee for Scientific Research (PBZ_KBN_122/P05/2004).
Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT BRCAs): Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program (CRN_87521); Canadian Breast Cancer Research Alliance (019511).
Istituto Oncologico Veneto—Hereditary Breast Ovarian Cancer Study: “Ministero della Salute” (RFPS 2006-5-341353, ACC2/R6.9).
KCONFAB: National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), and the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. A.B.S. and G.C.-T. are Senior and Senior Principal Research Fellows of the NHMRC, respectively.
Mayo Clinic Study: National Institutes of Health (R01 CA128978 and P50 CA116201); Komen race for the cure (KG081527); Breast Cancer Research Foundation.
Memorial Sloane Kettering Cancer Center: Breast Cancer Research Foundation and the Lomangino Family Research Fund.
NCI: Intramural Research Program of the US NCI at the National Institutes of Health; support services contracts (NO2-CP-11019-50 and N02-CP-65504 to P.L.M. and M.H.G.) with Westat, Inc, Rockville, MD.
N.N. Petrov Institute of Oncology: Russian Foundation for Basic Research (08-04-00369-a, 10-04-92110 and 10-04-92110-a); Federal Agency for Science and Innovations (contract 02.740.11.0780); Commission of the European Communities (PITN-GA-2009-238132); Royal Society International Joint (JP090615).
Ontario Cancer Genetics Network (OCGN): Supported by Cancer Care Ontario, Canada (I.L.A.); and the NCI, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and PIs. The content of this article does not necessarily reflect the views or policies of the NCI or any of the collaborating centers in the Cancer Family Registry (CFR) nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR.
Pisa Breast Cancer Study: Fondazione Cassa di Risparmio di Pisa (122/07) and grant 2010 from Istituto Toscano Tumori.
Swedish Breast Cancer Study (SWE-BRCA): Supported by the Swedish Cancer Society.
University of California Irvine: National Institutes of Health (R01 CA74415 to SLN and Y.C.D.).
University of California San Francisco (UCSF): Clinical and Translational Science Institute at the University of California, San Francisco (to M.S.B.).
UK and Gilda Radner Familial Ovarian Cancer Registries (UKGRFOCR): UKFOCR was supported by a project grant from CRUK to P.P. Some of this work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centre funding scheme.
University of Pennsylvania: Breast Cancer Research Foundation (K.L.N.); Cancer Genetics Network (HHSN21620074400C to S.M.D.).
Women’s Cancer Research Institute: Supported in part by the American Cancer Society Early Detection Professorship, L & S Milken Family Foundation, and Entertainment Industry Foundation.