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PMID: 17529967 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Genome-wide association study identifies novel breast cancer susceptibility loci.

Nature ·Vol. 447 ·No. 7148 ·2007-06-28 ·Pages 1087-93

Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S, Healey CS, Bowman R, SEARCH collaborators, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le Marchand L, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY, Wu PE, Wang HC, Eccles D, Evans DG, Peto J, Fletcher O, Johnson N, Seal S, Stratton MR, Rahman N, Chenevix-Trench G, Bojesen SE, Nordestgaard BG, Axelsson CK, Garcia-Closas M, Brinton L, Chanock S, Lissowska J, Peplonska B, Nevanlinna H, Fagerholm R, Eerola H, Kang D, Yoo KY, Noh DY, Ahn SH, Hunter DJ, Hankinson SE, Cox DG, Hall P, Wedren S, Liu J, Low YL, Bogdanova N, Schürmann P, Dörk T, Tollenaar RA, Jacobi CE, Devilee P, Klijn JG, Sigurdson AJ, Doody MM, Alexander BH, Zhang J, Cox A, Brock IW, MacPherson G, Reed MW, Couch FJ, Goode EL, Olson JE, Meijers-Heijboer H, van den Ouweland A, Uitterlinden A, Rivadeneira F, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Hopper JL, McCredie M, Southey M, Giles GG, Schroen C, Justenhoven C, Brauch H, Hamann U, Ko YD, Spurdle AB, Beesley J, Chen X, kConFab, AOCS Management Group, Mannermaa A, Kosma VM, Kataja V, Hartikainen J, Day NE, Cox DR, Ponder BA

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.

MeSH Terms
Alleles Apoptosis Regulatory Proteins Asia, Southeastern Australia Breast Neoplasms/genetics Case-Control Studies Europe/ethnology Female Genetic Predisposition to Disease/genetics Genome, Human/genetics Genotype High Mobility Group Proteins Humans MAP Kinase Kinase Kinase 1/genetics Microfilament Proteins/genetics North America Odds Ratio Polymorphism, Single Nucleotide/genetics Receptor, Fibroblast Growth Factor, Type 2/genetics Receptors, Progesterone/genetics Trans-Activators
Chemicals
Apoptosis Regulatory Proteins High Mobility Group Proteins LSP1 protein, human Microfilament Proteins Receptors, Progesterone TOX3 protein, human Trans-Activators FGFR2 protein, human Receptor, Fibroblast Growth Factor, Type 2 MAP Kinase Kinase Kinase 1 MAP3K1 protein, human
Authors & Affiliations
105 authors, click to expand affiliations / ORCID
Easton Douglas F
CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. [email protected]
Pooley Karen A
Dunning Alison M
Pharoah Paul D P
Thompson Deborah
Ballinger Dennis G
Struewing Jeffery P
Morrison Jonathan
Field Helen
Luben Robert
Wareham Nicholas
Ahmed Shahana
Healey Catherine S
Bowman Richard
SEARCH collaborators
Meyer Kerstin B
Haiman Christopher A
Kolonel Laurence K
Henderson Brian E
Le Marchand Loic
Brennan Paul
Sangrajrang Suleeporn
Gaborieau Valerie
Odefrey Fabrice
Shen Chen-Yang
Wu Pei-Ei
Wang Hui-Chun
Eccles Diana
Evans D Gareth
Peto Julian
Fletcher Olivia
Johnson Nichola
Seal Sheila
Stratton Michael R
Rahman Nazneen
Chenevix-Trench Georgia
Bojesen Stig E
Nordestgaard Børge G
Axelsson Christen K
Garcia-Closas Montserrat
Brinton Louise
Chanock Stephen
Lissowska Jolanta
Peplonska Beata
Nevanlinna Heli
Fagerholm Rainer
Eerola Hannaleena
Kang Daehee
Yoo Keun-Young
Noh Dong-Young
Ahn Sei-Hyun
Hunter David J
Hankinson Susan E
Cox David G
Hall Per
Wedren Sara
Liu Jianjun
Low Yen-Ling
Bogdanova Natalia
Schürmann Peter
Dörk Thilo
Tollenaar Rob A E M
Jacobi Catharina E
Devilee Peter
Klijn Jan G M
Sigurdson Alice J
Doody Michele M
Alexander Bruce H
Zhang Jinghui
Cox Angela
Brock Ian W
MacPherson Gordon
Reed Malcolm W R
Couch Fergus J
Goode Ellen L
Olson Janet E
Meijers-Heijboer Hanne
van den Ouweland Ans
Uitterlinden André
Rivadeneira Fernando
Milne Roger L
Ribas Gloria
Gonzalez-Neira Anna
Benitez Javier
Hopper John L
McCredie Margaret
Southey Melissa
Giles Graham G
Schroen Chris
Justenhoven Christina
Brauch Hiltrud
Hamann Ute
Ko Yon-Dschun
Spurdle Amanda B
Beesley Jonathan
Chen Xiaoqing
kConFab
AOCS Management Group
Mannermaa Arto
Kosma Veli-Matti
Kataja Vesa
Hartikainen Jaana
Day Nicholas E
Cox David R
Ponder Bruce A J
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature05887
Email
[email protected]
Published
2007-06-28
Pages
1087-93
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2714974
Subset
IM
Grants
Breast Cancer Now · 2004NOV49 · United Kingdom
Cancer Research UK · A3353 · United Kingdom
Breast Cancer Now · BREAST CANCER NOW RESEARCH CENTRE · United Kingdom
External Links
PubMed source DOI: 10.1038/nature05887 PMC Full Text View journal details
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