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Genome-wide association study identifies novel breast cancer susceptibility loci

Authors
Douglas Easton,Karen Pooley
Alison Dunning,Paul Pharoah,Deborah Thompson,Dennis Ballinger,Jeffery Struewing,Jonathan Morrison,Helen Field,Robert Luben,Nicholas Wareham,Shahana Ahmed,Catherine Healey,Adam Naguib,Craig Luccarini,Don Conroy,Mitul Shah,Hannah Munday,Clare Jordan,Barbara Perkins,Judy West,Karen Redman,Kristy Driver,Kerstin Meyer,Graham Mann,Laurence Kolonel,Brian Henderson,Loı̈c Marchand,Paul Brennan,Suleeporn Sangrajrang,Valérie Gaborieau,Fabrice Odefrey,Chen‐Yang Shen,Pei‐Ei Wu,Hui‐Chun Wang,Rosalind Eeles,D. Evans,Julian Peto,Olivia Fletcher,Nichola Johnson,Cecilia Lindgren,Michael Stratton,Nazneen Rahman,Georgia Chenevix‐Trench,Stig Bojesen,Børge Nordestgaard,C. Axelsson,Montserrat García‐Closas,Louise Brinton,Stephen Chanock,Jolanta Lissowska,Beata Pepłońska,Heli Nevanlinna,Rainer Fagerholm,Hannaleena Eerola,Daehee Kang,Dong‐Young Noh,Sei Ahn,David Wyld,Susan Hankinson,David Cox,Per Hall,Sara Wedrén,Jing Liu,Yen-Ling Low,Natalia Bogdanova,Peter Schürmann,Thilo Dörk,Rob Tollenaar,Catharina Jacobi,Peter Devilee,Jan Klijn,Alice Sigurdson,Michele Doody,Bruce Alexander,Jinghui Zhang,Angela Cox,Simon Cross,Gordon Macpherson,Malcolm Reed,Fergus Couch,Ellen Goode,Janet Olson,Hanne Meijers‐Heijboer,Ans Ouweland,André Uitterlinden,Fernando Rivadeneira,Roger Milne,Glòria Ribas,Anna González‐Neira,Javier Benı́tez,John Hopper,Margaret McCredie,Melissa Southey,Graham Giles,Chris Schroen,Christina Justenhoven,Hiltrud Brauch,Ute Hamann,Yon‐Dschun Ko,Amanda Spurdle,Jonathan Beesley,Xiaohong Chen,Morteza Aghmesheh,David Amor,Lesley Andrews,Jeffrey Weitzel,Jane Armes,Shane Armitage,Leanne Arnold,Rosemary Balleine,Glenn Begley,Ian Bennett,Barbara Bennett,Geoffrey Berry,Anneke Blackburn,Meagan Brennan,Melissa Brown,Michael Buckley,Jo Burke,Phyllis Butow,Keith Byron,David Callen,Ian Campbell,Christine Clarke,Alison Colley,Daniel Cotton,Jisheng Cui,Bronwyn Culling,Margaret Cummings,Sarah‐Jane Dawson,Joanne Dixon,Alexander Dobrovic,Tracy Dudding‐Byth,Ted Edkins,Maurice Eisenbruch,Gelareh Farshid,Susan Fawcett,Michael Field,F Firgaira,Jean Fleming,John Forbes,Michael Friedlander,Clara Gaff,Mary Gardner,Mike Gattas,Peter George,Grantley Gill,Jack Goldblatt,Sian Greening,G. Scott,Eric Haan,Thomas Hansen,Stewart Hart,Nicholas Hayward,Edward Humphrey,Mark Jenkins,Alison Jones,Richard Kefford,Sandrine Caputo,James Kollias,С. Коваленко,Sunil Lakhani,Jennifer Leary,Jacqueline Lim,Geoffrey Lindeman,Lara Lipton,Liz Lobb,Mariette Maclurcan,Deborah Marsh,R. McKay,A. Bowcock,Bettina Meiser,Gillian Mitchell,Beth Newman,Imelda O’Loughlin,Richard Osborne,Lester Peters,Kelly‐Anne Phillips,Jeanne Reeve,Tony Reeve,Robert Richards,Gina Rinehart,Bridget Robinson,Barney Rudzki,Elizabeth Salisbury,Joe Sambrook,Christobel Saunders,Clare Scott,Elizabeth Scott,Rodney Scott,R. Seshadri,Andrew Shelling,Graeme Suthers,Donna Taylor,Christopher Tennant,Heather Thorne,Sharron Townshend,Kathy Tucker,Janet Tyler,Deon Venter,Jane Visvader,Ian Walpole,Robyn Ward,Paul Waring,Beverley Warner,Graham Warren,Elizabeth Watson,Rachael Williams,Ju Oei,Ingrid Winship,Mary Young,David Bowtell,Adèle Green,Anna deFazio,Dorota Gertig,Penelope Webb,Anne‐Lise Børresen‐Dale,Veli‐Matti Kosma,Vesa Kataja,Jaana Hartikainen,Nicholas Day,Bruce Ponder,Rosemarie Davidson,Hanne Meijers-Heijboer
+223 authors
,John Beilby
Journal
Published
May 27, 2007
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Abstract

Breast 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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