Abstract
Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2 = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10-9 for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10-8 for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
| Original language | English |
|---|---|
| Pages (from-to) | 3304-3321 |
| Number of pages | 18 |
| Journal | Human Molecular Genetics |
| Volume | 20 |
| Issue number | 16 |
| DOIs | |
| State | Published - 1 Aug 2011 |
| Externally published | Yes |
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In: Human Molecular Genetics, Vol. 20, No. 16, 01.08.2011, p. 3304-3321.
Research output: Contribution to journal › Article › peer-review
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T1 - Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
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AU - Barile, Monica
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AU - Byrski, Tomasz
AU - Cybulski, Cezary
AU - Gorski, Bohdan
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AU - Cajal, Teresa Ramón
AU - Fostira, Florentia
AU - Andrés, Raquel
AU - Benitez, Javier
AU - Hamann, Ute
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AU - Rookus, Matti A.
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AU - Nelen, Marcel R.
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AU - Cook, Jackie
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AU - Miedzybrodzka, Zosia
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AU - Stoppa-Lyonnet, Dominique
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AU - Tirapo, Carole
AU - Mazoyer, Sylvie
AU - Barjhoux, Laure
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AU - Nogues, Catherine
AU - Rouleau, Etienne
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AU - Coupier, Isabelle
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AU - Gadzicki, Dorothea
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AU - de la Hoya, Miguel
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AU - Dumont, Martine
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AU - Tischkowitz, Marc
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AU - Beesley, Jonathan
AU - Spurdle, Amanda B.
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AU - Ding, Yuan Chun
AU - Fredericksen, Zachary
AU - Wang, Xianshu
AU - Pankratz, Vernon S.
AU - Couch, Fergus
AU - Simard, Jacques
AU - Easton, Douglas F.
AU - Chenevix-Trench, Georgia
AU - Karlsson, Per
AU - Nordling, Margareta
AU - Bergman, Annika
AU - Einbeigi, Zakaria
AU - Stenmark-Askmalm, Marie
AU - Liedgren, Sigrun
AU - Borg, Ake
AU - Olsson, Håkan
AU - Kristoffersson, Ulf
AU - Jernström, Helena
AU - Henriksson, Karin
AU - von Wachenfeldt, Anna
AU - Liljegren, Annelie
AU - Barbany-Bustinza, Gisela
AU - Rantala, Johanna
AU - Grönberg, Henrik
AU - Stattin, Eva Lena
AU - Emanuelsson, Monica
AU - Brandell, Richard Rosenquist
AU - Dahl, Niklas
AU - Verhoef, S.
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AU - Veer, L. J.van t.
AU - van Leeuwen, F. E.
AU - Collée, M.
AU - van den Ouweland, A. M.W.
AU - Jager, A.
AU - Tilanus-Linthorst, M. M.A.
AU - Seynaeve, C.
AU - Wijnen, J. T.
AU - Vreeswijk, M. P.
AU - Tollenaar, R. A.
AU - Ligtenberg, M. J.
AU - Hoogerbrugge, N.
AU - Ausems, M. G.
AU - Aalfs, C. M.
AU - van Os, Theo A.M.
AU - Gille, J. J.P.
AU - Waisfisz, Q.
AU - Gomez-Garcia, E. B.
AU - van Roozendaal, C. E.
AU - Blok, Marinus J.
AU - Caanen, B.
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AU - Jobson, Irene
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AU - Houlston, Richard
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AU - D'Mello, Lucia
AU - Page, Elizabeth
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AU - Wiggins, Jennifer
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AU - Hodgson, Shirley
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N1 - Funding Information: UK and Gilda Radner Familial Ovarian Cancer Registries (UKGRFOCR) UKFOCR was supported by a project grant from CR-UK to Paul Pharoah. We thank Simon Gayther, Susan Ramus, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. We would like to acknowledge the Roswell Park Alliance Foundation for their continued support of the Gilda Radner Ovarian Family Cancer Registry. GRFOCR would like to acknowledge Kirsten Moysich (Department of Cancer Prevention and Control) and Kunle Odunsi (Departments Gynecologic Oncology and Immunology). University California San Francisco study (USCF) Dr Beattie was supported by a grant from the National Institutes of Health, National Cancer Institute, Bay Area Breast SPORE (P50 CA058207) UPENN SMD receives funding from the MacDonald Family Foundation, and KLN from Breast Cancer Research Foundation. TR is funded by NIH grants R01-CA102776 and R01-CA083855. Cedars-Sinai Medical Center (WCRI) This work was supported by the American Cancer Society Early Detection Professorship and Entertainment Industry Foundation. Funding Information: A.C.A. is a CR-UK Senior Cancer Research Fellow, D.F.E. is CR-UK Principal Research Fellow and G.C.T. is a NHMRC Senior Principal Research Fellow. Study-specific acknowledgments: The Baltic Familial Breast and Ovarian Cancer Consortium (BFBOCC) Dr Laima Tihomirova, the Genome Database of the Latvian Population, Latvian Biomedical Research and Study Centre provided data and DNA samples for BFBOCC. This work is supported by the Research Council of Lithuania grant LIG-19/2010 to Ramunas Janavicius. Funding Information: HEBON Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.B.L. Hoger-vorst, S. Verhoef, M. Verheus, L.J. van ‘t Veer, F.E. van Leeuwen, M.A. Rookus; Erasmus Medical Center, Rotterdam, NL: M. Collée, A.M.W. van den Ouweland, A. Jager, M.J. Hooning, M.M.A. Tilanus-Linthorst, C. Seynaeve; Leiden University Medical Center, NL, Leiden: C.J. van Asperen, J.T. Wijnen, M.P. Vreeswijk, R.A. Tollenaar, P. Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: M.J. Ligtenberg, N. Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: M.G. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL: C.M. Aalfs, T.A. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: E.B. Gomez-Garcia, C.E. van Roozendaal, Marinus J. Blok, B. Caanen; University Medical Center Groningen University, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088 and NKI2007-3756. Funding Information: The study is supported by grants from the Cancer Association of South Africa to Elizabeth J. van Rensburg. Breast Cancer Family Registry (BCFR) This work was supported by the National Cancer Institute, National Institutes of Health 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). Samples from the FCCC, HCI and CPIC were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres 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) We thank Susanne Kjaergaard and Mette Klarskov for clinical data. The study was supported by the NEYE Foundation. CONSIT TEAM CONSIT TEAM is supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006 ‘Alleanza contro il Cancro’ to LV and PR and ‘Progetto Tumori Femminili’ to PR), Ministero dell’Universita’ e Ricerca (RBLAO3-BETH to PR), Fondazione Italiana per la Ricerca sul Cancro (Special Project ‘Hereditary tumors’ to PR), Associazione Italiana per la Ricerca sul Cancro (4017) to PP and by funds from Italian citizens who allocated the 5 ×1000 share of their tax payment in support of the Fonda-zione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5×1000’) to P.P. Funding Information: Istituto Oncologico Veneto—Hereditary Breast Ovarian Cancer Study (IOVHBOCS) This study was supported by ‘Ministero della Salute’ (grant numbers RFPS 2006-5-341353, ACC2/R6.9 and ‘Progetto Tumori Femminili’). Funding Information: The study is 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. We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, & UMR5201 CNRS, Université de Lyon, Lyon: Olga Sinilnikova, Laure Barjhoux, Carole Verny-Pierre, Sophie Giraud, Mélanie Léone, Sylvie Mazoyer; and Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Carole Tirapo, Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Audrey Remenieras, Véronique Byrde, Olivier Caron, Gilbert Lenoir. Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon, Nancy Uhrham-mer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona. Centre Franc¸ois Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Franc¸ois Eisinger. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Franc¸oise Révillion, Philippe Vennin, Claude Adenis. Hôpital René Huguenin/Institut Curie, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung. CHU de Dijon: Fanny Coron, Laurence Faivre. CHU de St-Etienne: Fabienne Prieur, Marine Lebrun. Hôtel Dieu Centre Hospita-lier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacas-sagne, Nice: Marc Frénay. CHU de Limoges: Laurence Vénat-Bouvet. CHU de Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Creighton University, Omaha, USA: Henry T.Lynch, Carrie L.Snyder. Gynecologic Oncology Group (GOG) GOG’s participation was supported through funding provided by both intramural (Clinical Genetics Branch, DCEG) and extramural (Community Oncology and Prevention Trials Program—COPTRG) NCI programs. Hospital Clinico San Carlos This work was supported by the ISCIII grant RD06/0020/ 0021. Helsinki Breast Cancer Study (HEBCS) The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society and the Sigrid Juselius Foundation. We thank Tuomas Heikki-nen and RN Irja Erkkilä for their help with the patient data and study samples. Funding Information: SWE-BRCA collaborators: Per Karlsson, Margareta Nord-ling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren, Linköping University Hospital; Åke Borg, Niklas Loman, Håkan Olsson, Ulf Kristoffersson, Helena Jernström, Katja Harbst and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Grönberg, Eva-Lena Stattin and Monica Emanuelsson, Umeå University Hospital; Hans Ehren-crona, Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital. University of California Irvine Study (UCI) Now at the Beckman Research Institute of the City of Hope. This work was supported by NIH grant R01-CA74415 (to SLN). SLN is partially supported by the Morris and Horowitz Families Endowed Professorship. Funding Information: The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) GC-HBOC is supported by a grant of the German Cancer Aid (grant 107054). We thank Christian Sutter (Center Heidelberg) Sabine Preisler-Adams (Center Münster), Britta Fiebig (Center Regensburg), Wolfram Heinritz (Center Leipzig) and Dieter Schäfer (Center Frankfurt) for providing samples and Juliane Köhler for her excellent technical assistance. Funding Information: The Ohio State University Clinical Cancer Genetics (OSU CCG) This work was supported by the Ohio State University Comprehensive Cancer Center. We thank Leigha Senter and Kevin Sweet for patient accrual and data management, the Human Genetics Sample bank for sample preparation and the OSU CCC Nucleic Acids Shared Resource for genotyping plate reads. Pisa Breast Cancer Study (PBCS) MAC from University Hospital of Pisa was supported by Istituto Toscano Tumori grant SEABASS SEABASS is a collaborative effort between Cancer Research Initiatives Foundation (Malaysia), University Malaya (Malaysia), National University Hospital (Singapore), University Kebangsaan Malaysia (Malaysia), Hospital Kuala Lumpur (Malaysia) and Putrajaya Hospital (Malaysia). The research has received funding from CARIF and University Malaya. Funding Information: Hungarian Breast and Ovarian Cancer Study (HUNBOCS) This work was supported by Hungarian Research Grant NKTH-OTKA CK-80745 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/ÖP-9. INHERIT Jacques Simard, Francine Durocher, Rachel Laframboise, Marie Plante, Centre Hospitalier Universitaire de Quebec & Laval University, Quebec, Canada ; Peter Bridge, Jilian Parboosingh, Molecular Diagnostic Laboratory, Alberta Children’s Hospital, Calgary, Canada; Jocelyne Chiquette, Hôpital du Saint-Sacrement, Quebec, Canada ; Bernard Les-perance, Hôpital du Sacré-Cœur de Montréal, Montréal, Canada. Jacques Simard—J.S. is Chairholder of the Canada Research Chair in Oncogenetics. This work was supported 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. ILUH The study was supported by the Icelandic Association ‘Walking for Breast Cancer Research’ and by the Landspitali University Hospital Research Fund. Funding Information: This work was supported by Cancer Research 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-F22009-223175). Funding Information: Kathleen Cuningham Consortium for Research into Familial Breast Cancer (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 (funded by NHMRC grants 145684, 288704 and 454508) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is 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. ABS is supported by an NHMRC Senior Research Fellowship. McGill This work was supported by the Jewish General Hospital Weekend to End Breast Cancer. MT holds a Fonds de la Recherche en Santé du Québec clinician-scientist award. National Cancer Institute (NCI) The research of Drs PL Mai and MH Greene was supported by the Intramural Research Program of the US National Cancer Institute, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. Mayo Clinic (MAYO) This work was supported by grants from the Breast Cancer Research Foundation (BCRF), Komen Foundation for the Cure, Department of Defense ovarian cancer research award (W81XWH-10-1-0341) and US National Cancer Institute, National Institutes of Health grant CA128978. N.N. Petrov Institute of Oncology (NNPIO) The work is supported by the Russian Foundation for Basic Research (grants 08-04-00369-a, 09-04-90402 and 10-04-92110-a), the Commission of the European Communities (grant PITN-GA-2009-238132) and through a Royal Society International Joint grant (JP090615). Ontario Cancer Genetics Network (OCGN) This work was supported by Cancer Care Ontario and the US National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute 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. We wish to thank Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study. Funding Information: Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE) Douglas Easton is the PI of the study. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Debra Frost, Radka Platte, Jean Leyland. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Carole McKeown, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy’s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D’Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are 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. Ros Eeles, Elizabeth Bancroft and Lucia D’Mello are also supported by Cancer Research UK Grant C5047/A8385. Deutsches Krebsforschungszentrum (DKFZ) study The DKFZ study was supported by the DKFZ.
PY - 2011/8/1
Y1 - 2011/8/1
N2 - Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2 = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10-9 for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10-8 for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
AB - Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2 = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10-9 for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10-8 for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
UR - http://www.scopus.com/inward/record.url?scp=79960819760&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddr226
DO - 10.1093/hmg/ddr226
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AN - SCOPUS:79960819760
SN - 0964-6906
VL - 20
SP - 3304
EP - 3321
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 16
ER -