Genome-wide association study identifies novel breast cancer susceptibility loci
2007; Nature Portfolio; Volume: 447; Issue: 7148 Linguagem: Inglês
10.1038/nature05887
ISSN1476-4687
AutoresDouglas F. Easton, Karen A. Pooley, Alison M. Dunning, Paul D.P. Pharoah, Deborah J. Thompson, Dennis G. Ballinger, Jeffery P. Struewing, Jonathan J. Morrison, Helen I. Field, Robert Luben, Nicholas J. Wareham, Shahana Ahmed, Catherine S. Healey, Richard Bowman, Craig Luccarini, Don Conroy, Mitul Shah, Hannah Munday, Clare Jordan, Barbara Perkins, Judy West, Karen Redman, Kristy Driver, Kerstin B. Meyer, Christopher A. Haiman, Laurence Kolonel, Brian E. Henderson, Loı̈c Le Marchand, Paul Brennan, Suleeporn Sangrajrang, Valérie Gaborieau, Fabrice Odefrey, Chen‐Yang Shen, Pei‐Ei Wu, Hui‐Chun Wang, Diana Eccles, D. Gareth Evans, Julian Peto, Olivia Fletcher, Nichola Johnson, Sheila Seal, Michael R. Stratton, Nazneen Rahman, Georgia Chenevix‐Trench, Stig E. Bojesen, Børge G. Nordestgaard, C. K. Axelsson, Montserrat García‐Closas, Louise A. Brinton, Stephen J. Chanock, Jolanta Lissowska, Beata Pepłońska, Heli Nevanlinna, Rainer Fagerholm, Hannaleena Eerola, Daehee Kang, Keun-Young Yoo, Dong‐Young Noh, Sei Hyun Ahn, David J. Hunter, Susan E. Hankinson, David G. Cox, Per Hall, Sara Wedrén, Jianjun Liu, Yen-Ling Low, Natalia Bogdanova, Peter Schürmann, Thilo Dörk, Rob A.�E.�M. Tollenaar, Catharina E. Jacobi, Peter Devilee, Jan G.M. Klijn, Alice J. Sigurdson, Michele M. Doody, Bruce H. Alexander, Jinghui Zhang, Angela Cox, Ian W. Brock, Gordon R. Macpherson, Malcolm Reed, Fergus J. Couch, Ellen L. Goode, Janet E. Olson, Hanne Meijers‐Heijboer, Ans van den Ouweland, André G. Uitterlinden, Fernando Rivadeneira, Roger L. Milne, Glòria Ribas, Anna González‐Neira, Javier Benı́tez, John L. Hopper, Margaret McCredie, Melissa C. Southey, Graham G. Giles, Chris Schroen, Christina Justenhoven, Hiltrud Brauch, Ute Hamann, Yon‐Dschun Ko, Amanda B. Spurdle, Jonathan Beesley, Xiaohong Chen, Morteza Aghmesheh, David J. Amor, Lesley Andrews, Yoland Antill, Jane E. Armes, Shane Armitage, Leanne Arnold, Rosemary L. Balleine, Glenn Begley, John Beilby, Ian Bennett, Barbara Bennett, Geoffrey Berry, Anneke C. Blackburn, Meagan Brennan, Melissa A. Brown, Michael Buckley, Jo Burke, Phyllis Butow, Keith Byron, David F. Callen, Ian Campbell, Georgia Chenevix‐Trench, Christine L. Clarke, Alison Colley, Dick Cotton, Jisheng Cui, Bronwyn Culling, Margaret C. Cummings, Sarah‐Jane Dawson, Joanne Dixon, Alexander Dobrovic, Tracy Dudding, Ted Edkins, Maurice Eisenbruch, Gelareh Farshid, Susan Fawcett, Michael Field, F A Firgaira, Jean S. Fleming, John Forbes, Michael Friedlander, Clara Gaff, M.D. Gardner, Mike Gattas, Peter George, Graham G. Giles, Grantley Gill, Jack Goldblatt, Sian Greening, Scott Grist, Eric Haan, Marion Harris, Stewart Hart, Nicholas K. Hayward, John L. Hopper, Evelyn Humphrey, Mark A. Jenkins, Alison Jones, Richard Kefford, Judy Kirk, James Kollias, С. П. Коваленко, Sunil R. Lakhani, Jennifer Leary, Jacqueline Lim, Geoffrey J. Lindeman, Lara Lipton, Liz Lobb, Mariette Maclurcan, Graham J. Mann, Deborah J. Marsh, Margaret McCredie, R. Michael L. McKay, Sue Anne McLachlan, Bettina Meiser, Roger L. Milne, Gillian Mitchell, Beth Newman, Imelda O’Loughlin, Richard H. Osborne, Lester Peters, Kelly‐Anne Phillips, Melanie A. Price, Jeanne Reeve, Tony Reeve, Robert I. Richards, Gina Rinehart, Bridget A. Robinson, Barney Rudzki, Elizabeth Salisbury, Joe Sambrook, Christobel Saunders, Clare L. Scott, Elizabeth Scott, Rodney J. Scott, R. Seshadri, Andrew N. Shelling, Melissa C. Southey, Amanda B. Spurdle, Graeme Suthers, Donna Taylor, Christopher Tennant, Heather Thorne, Sharron Townshend, Kathy Tucker, Janet Tyler, Deon J. Venter, Jane E. Visvader, Ian Walpole, Robyn L. Ward, Paul Waring, B Warner, Graham Warren, Elizabeth Watson, Rachael Williams, Judy Wilson, Ingrid Winship, Mary Ann Young, David D.L. Bowtell, Adèle C. Green, Anna deFazio, Georgia Chenevix‐Trench, Dorota M. Gertig, Penelope M. Webb, Graham J. Mann, Veli‐Matti Kosma, Vesa Kataja, Jaana M. Hartikainen, Nicholas Day, David R. Cox, Bruce A.J. Ponder,
Tópico(s)Epigenetics and DNA Methylation
ResumoBreast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. Until the genome-wide association study on page 1087 was published online, known susceptibility genes — such as BRCA1 and BRCA2 — accounted for less than 25% of the familial risk of breast cancer. The new study, which involved 21,860 patients and 22,578 controls, has identified four genes positively associated with genetic susceptibility to breast cancer (FGFR2, TNRC9, MAP3K1 and LSP1). Most previously identified breast cancer susceptibility genes are involved in DNA repair, but the newly discovered associations appear to relate more to the control of cell growth or to cell signalling. Only one of the genes — FGFR2 — had a clear prior relevance to breast cancer. The identification of these genes opens up new avenues of research into the causes of breast cancer. They may also become part of a new strategy to classify women's risk, paving the way for better disease prevention. Previous work has identified several genes where mutations lead to breast cancer, but other genetic and environmental factors must still be accounted for. A large study of genetic association with breast cancer points to four novel genes and many more genetic markers that should be pursued for their link to cancer susceptibility.
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