A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).
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.
Thomas
Gilles
G
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
KB
Kraft
Peter
P
Yeager
Meredith
M
Wacholder
Sholom
S
Cox
David G
DG
Hankinson
Susan E
SE
Hutchinson
Amy
A
Wang
Zhaoming
Z
Yu
Kai
K
Chatterjee
Nilanjan
N
Garcia-Closas
Montserrat
M
Gonzalez-Bosquet
Jesus
J
Prokunina-Olsson
Ludmila
L
Orr
Nick
N
Willett
Walter C
WC
Colditz
Graham A
GA
Ziegler
Regina G
RG
Berg
Christine D
CD
Buys
Saundra S
SS
McCarty
Catherine A
CA
Feigelson
Heather Spencer
HS
Calle
Eugenia E
EE
Thun
Michael J
MJ
Diver
Ryan
R
Prentice
Ross
R
Jackson
Rebecca
R
Kooperberg
Charles
C
Chlebowski
Rowan
R
Lissowska
Jolanta
J
Peplonska
Beata
B
Brinton
Louise A
LA
Sigurdson
Alice
A
Doody
Michele
M
Bhatti
Parveen
P
Alexander
Bruce H
BH
Buring
Julie
J
Lee
I-Min
IM
Vatten
Lars J
LJ
Hveem
Kristian
K
Kumle
Merethe
M
Hayes
Richard B
RB
Tucker
Margaret
M
Gerhard
Daniela S
DS
Fraumeni
Joseph F
JF
Hoover
Robert N
RN
Chanock
Stephen J
SJ
Hunter
David J
DJ