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PMID: 19330030 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).

Nature genetics ·Vol. 41 ·No. 5 ·2009-05-00 ·Pages 579-84

Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K, Chatterjee N, Garcia-Closas M, Gonzalez-Bosquet J, Prokunina-Olsson L, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver R, Prentice R, Jackson R, Kooperberg C, Chlebowski R, Lissowska J, Peplonska B, Brinton LA, Sigurdson A, Doody M, Bhatti P, Alexander BH, Buring J, Lee IM, Vatten LJ, Hveem K, Kumle M, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF, Hoover RN, Chanock SJ, Hunter DJ

Abstract

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

MeSH Terms
Alleles Breast Neoplasms/genetics Chromosomes, Human, Pair 1/genetics Chromosomes, Human, Pair 14/genetics DNA-Binding Proteins/genetics Female Genetic Predisposition to Disease Genome, Human Genome-Wide Association Study Genotype Humans Linkage Disequilibrium Polymorphism, Single Nucleotide
Chemicals
DNA-Binding Proteins RAD51B protein, human
Authors & Affiliations
48 authors, click to expand affiliations / ORCID
Thomas Gilles
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Jacobs Kevin B
Kraft Peter
Yeager Meredith
Wacholder Sholom
Cox David G
Hankinson Susan E
Hutchinson Amy
Wang Zhaoming
Yu Kai
Chatterjee Nilanjan
Garcia-Closas Montserrat
Gonzalez-Bosquet Jesus
Prokunina-Olsson Ludmila
Orr Nick
Willett Walter C
Colditz Graham A
Ziegler Regina G
Berg Christine D
Buys Saundra S
McCarty Catherine A
Feigelson Heather Spencer
Calle Eugenia E
Thun Michael J
Diver Ryan
Prentice Ross
Jackson Rebecca
Kooperberg Charles
Chlebowski Rowan
Lissowska Jolanta
Peplonska Beata
Brinton Louise A
Sigurdson Alice
Doody Michele
Bhatti Parveen
Alexander Bruce H
Buring Julie
Lee I-Min
Vatten Lars J
Hveem Kristian
Kumle Merethe
Hayes Richard B
Tucker Margaret
Gerhard Daniela S
Fraumeni Joseph F
Hoover Robert N
Chanock Stephen J
Hunter David J
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.353
Published
2009-05-00
Epub
2009-00-29
Pages
579-84
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2928646
Subset
IM
Grants
NCI NIH HHS · R01 CA050385 · United States
NCI NIH HHS · 5UO1CA098233 · United States
NCI NIH HHS · R01 CA065725-14 · United States
NCI NIH HHS · P01 CA087969 · United States
NCI NIH HHS · R01 CA067262 · United States
NCI NIH HHS · CA87969 · United States
NCI NIH HHS · CA49449 · United States
NCI NIH HHS · CA67262 · United States
NCI NIH HHS · U01 CA049449 · United States
NCI NIH HHS · U01 CA067262 · United States
NCI NIH HHS · R01 CA065725 · United States
NCI NIH HHS · U01 CA098233 · United States
Intramural NIH HHS · United States
NCI NIH HHS · R01 CA049449 · United States
NCI NIH HHS · UO1 CA098710 · United States
NCI NIH HHS · CA50385 · United States
NCI NIH HHS · U01 CA098710 · United States
NCI NIH HHS · CA65725 · United States
External Links
PubMed source DOI: 10.1038/ng.353 PMC Full Text View journal details
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