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

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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 × 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 × 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.

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Figure 1: Linkage disequilibrium plots of two newly discovered loci.
Figure 2: Forest plots for overall, ER-positive and ER-negative analyses for rs1124933 and rs999737.


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The Nurses' Health Studies are supported by US National Institutes of Health grants CA65725, CA87969, CA49449, CA67262, CA50385 and 5UO1CA098233. We thank B. Egan, L. Egan, H. Judge Ellis, H. Ranu and P. Soule for assistance, and the participants in the Nurses' Health Studies. The WHI program is supported by contracts from the National Heart, Lung and Blood Institute, NIH. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at http://www.whi.org. The ACS study is supported by UO1 CA098710. We thank C. Lichtman for data management and the participants on the CPS-II. The US Radiologic Technologists Study (USRT) is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS. The PLCO study is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. We thank P. Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and T. Sheehy and staff at SAIC-Frederick. We acknowledge the study participants for their contributions to making this study possible. We thank the radiologic technologists who participated in the study; J. Reid of the American Registry of Radiologic Technologists for continued support of the study; D. Kampa and A. Iwan of the University of Minnesota for study coordination and data collection; B. Kopp and staff at SAIC-Frederick for biospecimen processing; and L. Bowen of Information Management Systems for data management.

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Correspondence to David J Hunter.

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