Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Antonis C. Antoniou*, Christiana Kartsonaki, Olga M. Sinilnikova, Penny Soucy, Lesley McGuffog, Sue Healey, Andrew Lee, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Monica Barile, Valeria Pensotti, Barbara Pasini, Riccardo Dolcetti, Giuseppe Giannini, Anna Laura Putignano, Liliana Varesco, Paolo RadicePhuong L. Mai, Mark H. Greene, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne Marie Gerdes, Torben A. Kruse, Uffe Birk Jensen, Dorthe G. Crüger, Maria A. Caligo, Yael Laitman, Roni Milgrom, Bella Kaufman, Shani Paluch-Shimon, Eitan Friedman, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Hans Ehrencrona, Beatrice Melin, Katherine L. Nathanson, Susan M. Domchek, Timothy Rebbeck, Ania Jakubowska, Jan Lubinski, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Gorski, Ana Osorio, Teresa Ramón Cajal, Florentia Fostira, Raquel Andrés, Javier Benitez, Ute Hamann, Frans B. Hogervorst, Matti A. Rookus, Maartje J. Hooning, Marcel R. Nelen, R. B. van der Luijt, Theo A.M. van Os, C. J. van Asperen, P. Devilee, H. E.J. Meijers-Heijboer, Encarna B.Gómez Garcia, Susan Peock, Margaret Cook, D. Frost, Radka Platte, Jean Leyland, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Diana Eccles, Kai ren Ong, Jackie Cook, Fiona Douglas, Joan Paterson, M. John Kennedy, Zosia Miedzybrodzka, Andrew Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Muriel Belotti, Carole Tirapo, Sylvie Mazoyer, Laure Barjhoux, Christine Lasset, Dominique Leroux, Laurence Faivre, Myriam Bronner, Fabienne Prieur, Catherine Nogues, Etienne Rouleau, Pascal Pujol, Isabelle Coupier, Marc Frénay, John L. Hopper, Mary B. Daly, Mary B. Terry, Esther M. John, Saundra S. Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F. Singer, Muy Kheng Tea, Georg Pfeiler, Anne Catharina Dressler, Thomas v.O. Hansen, Lars Jønson, Bent Ejlertsen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Kenneth Offit, Marion Piedmonte, Gustavo Rodriguez, Laurie Small, John Boggess, Stephanie Blank, Jack Basil, Masoud Azodi, Amanda Ewart Toland, Marco Montagna, Silvia Tognazzo, Simona Agata, Evgeny Imyanitov, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Paul D.P. Pharoah, Lara Sucheston, Beth Y. Karlan, Christine S. Walsh, Edith Olah, Aniko Bozsik, Soo Hwang Teo, Joyce L. Seldon, Mary S. Beattie, Elizabeth J. van Rensburg, Michelle D. Sluiter, Orland Diez, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Ina Ruehl, Raymonda Varon-Mateeva, Karin Kast, Helmut Deissler, Dieter Niederacher, Norbert Arnold, Dorothea Gadzicki, Ines Schönbuchner, Trinidad Caldes, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Martine Dumont, Jocelyne Chiquette, Marc Tischkowitz, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan Chun Ding, Zachary Fredericksen, Xianshu Wang, Vernon S. Pankratz, Fergus Couch, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Per Karlsson, Margareta Nordling, Annika Bergman, Zakaria Einbeigi, Marie Stenmark-Askmalm, Sigrun Liedgren, Ake Borg, Håkan Olsson, Ulf Kristoffersson, Helena Jernström, Karin Henriksson, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza, Johanna Rantala, Henrik Grönberg, Eva Lena Stattin, Monica Emanuelsson, Richard Rosenquist Brandell, Niklas Dahl, S. Verhoef, M. Verheus, L. J.van t. Veer, F. E. van Leeuwen, M. Collée, A. M.W. van den Ouweland, A. Jager, M. M.A. Tilanus-Linthorst, C. Seynaeve, J. T. Wijnen, M. P. Vreeswijk, R. A. Tollenaar, M. J. Ligtenberg, N. Hoogerbrugge, M. G. Ausems, C. M. Aalfs, Theo A.M. van Os, J. J.P. Gille, Q. Waisfisz, E. B. Gomez-Garcia, C. E. van Roozendaal, Marinus J. Blok, B. Caanen, J. C. Oosterwijk, A. H. van der Hout, M. J. Mourits, H. F. Vasen, Helen Gregory, Patrick Morrison, Lisa Jeffers, Trevor Cole, Carole McKeown, Jonathan Hoffman, Alan Donaldson, Sarah Downing, Amy Taylor, Alexandra Murray, Mark T. Rogers, Emma McCann, David Barton, Mary Porteous, Sarah Drummond, Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan, Chris Jacobs, Caroline Langman, Anna Whaite, Huw Dorkins, Julian Barwell, Carol Chu, Julie Miller, Ian Ellis, Catherine Houghton, Jane Taylor, Lucy Side, Alison Male, Cheryl Berlin, Jacqueline Eason, Rebecca Collier, Oonagh Claber, Irene Jobson, Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner, 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, Oliver Quarrell, Cathryn Bardsley, Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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 languageEnglish
Pages (from-to)3304-3321
Number of pages18
JournalHuman Molecular Genetics
Volume20
Issue number16
DOIs
StatePublished - 1 Aug 2011
Externally publishedYes

Funding

FundersFunder number
Fondazione Italiana per la Ricerca sul Cancro
Landspítali Háskólasjúkrahús
Jewish General Hospital Weekend
MacDonald Family Foundation
National Breast Cancer Foundation
Ohio State University Comprehensive Cancer Center
Istituto Toscano Tumori
Cancer Association of South Africa to Elizabeth J. van Rensburg
CIHR Team in Familial Risks of Breast Cancer’ program
Breast Cancer Research Foundation
Ligue Contre le Cancer
Morris and Horowitz Families Endowed
Roswell Park Alliance Foundation, Roswell Park Cancer Institute
Universiti Malaya
Research Triangle Institute Informatics Support Center
Ohio State University Clinical Cancer Genetics
Istituto Oncologico Veneto
Icelandic Association
Universiti Kebangsaan Malaysia
National Institute for Health Research
Entertainment Industry Foundation
Neye Foundation
Hospital Kuala Lumpur
Cancer Prevention Institute of California
Jeju National University Hospital
Putrajaya Hospital
Cancer Foundation of Western Australia
Fonds de la Recherche en Santé du Québec clinician-scientist
Cancer Research Initiatives Foundation
American Cancer Society
Helsingin ja Uudenmaan Sairaanhoitopiiri
Cancer Council NSW
German Cancer Research Center
Finnish Cancer Society
USCF
CARIF
Sigrid Juséliuksen Säätiö
Cancer Council Queensland
National Institutes of HealthR01-CA102776, R01-CA74415, RFA-CA-06-503, CA128978, R01-CA083855
Association for International Cancer ResearchAICR-07-0454
Deutsche Krebshilfe107054
RFPN02PC45022-46
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer ResearchC5047/A8385
Ministero dell’Universita’ e RicercaRBLAO3-BETH
Ministero della SaluteACC2/R6.9, RFPS 2006-5-341353
Research Council of Finland132473
Cancer Research UKC1287/A11990, C12292/A11174, C1287/A10118
Associazione Italiana per la Ricerca sul Cancro4017
Cancer Care OntarioCA-06-503, U01 CA69467
Seventh Framework Programme223175, HEALTH-F22009-223175
Russian Foundation for Basic Research10-04-92110-a, 09-04-90402, 08-04-00369-a
Huntsman Cancer InstituteU01 CA69446
Royal SocietyJP090615
Instituto de Salud Carlos IIIRD06/0020/ 0021
Dutch Cancer SocietyNKI1998-1854, NKI2004-3088, NKI2007-3756
Columbia UniversityU01 CA69398
Lietuvos Mokslo TarybaLIG-19/2010
University of MelbourneU01 CA69638
Canadian Institutes of Health Research019511
Norwegian EEA Financial MechanismHu0115/NA/2008-3/ÖP-9
Fox Chase Cancer CenterU01 CA69631
National Health and Medical Research Council454508
National Cancer InstituteNO2-CP-11019-50, P50 CA058207, N02-CP-65504
Komen Foundation for the Cure, Department of DefenseW81XWH-10-1-0341
European CommissionPITN-GA-2009-238132
Northern California Cancer CenterU01 CA69417

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