Letter abstract
Nature Genetics 41, 579 - 584 (2009)
Published online: 29 March 2009 | doi:10.1038/ng.353
A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)
Gilles Thomas1, Kevin B Jacobs1,2,3, Peter Kraft4, Meredith Yeager1,3, Sholom Wacholder1, David G Cox4,5, Susan E Hankinson5, Amy Hutchinson1,3, Zhaoming Wang1,3, Kai Yu1, Nilanjan Chatterjee1, Montserrat Garcia-Closas1, Jesus Gonzalez-Bosquet1, Ludmila Prokunina-Olsson1, Nick Orr1, Walter C Willett5,6, Graham A Colditz7, Regina G Ziegler1, Christine D Berg8, Saundra S Buys9, Catherine A McCarty10, Heather Spencer Feigelson11, Eugenia E Calle11, Michael J Thun11, Ryan Diver11, Ross Prentice12, Rebecca Jackson13, Charles Kooperberg12, Rowan Chlebowski14, Jolanta Lissowska15, Beata Peplonska16, Louise A Brinton1, Alice Sigurdson1, Michele Doody1, Parveen Bhatti1, Bruce H Alexander17, Julie Buring18, I-Min Lee18, Lars J Vatten19, Kristian Hveem19, Merethe Kumle20, Richard B Hayes1, Margaret Tucker1, Daniela S Gerhard21, Joseph F Fraumeni Jr1, Robert N Hoover1, Stephen J Chanock1 & David J Hunter1,4,5,6,22
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.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
- Bioinformed Consulting Services, Gaithersburg, Maryland, USA.
- Core Genotyping Facility, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland, USA.
- Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
- Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
- Washington University School of Medicine, St. Louis, Missouri, USA.
- Division of Cancer Prevention, NCI, NIH, DHHS, Bethesda, Maryland, USA.
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
- The Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
- Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia, USA.
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Division of Diabetes, Endocrinology and Metabolism, The Ohio State University Medical Center, Columbus, Ohio, USA.
- Harbor-University of California at Los Angeles Medical Center, Torrance, California, USA.
- Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
-
Nofer Institute of Occupational Medicine,
ód
, Poland. - Division of Environmental Health Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
- Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
- Institute of Community Medicine, University of Tromso, Tromso, Norway.
- Office of Cancer Genomics, NCI, NIH, DHHS Bethesda, Maryland, USA.
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Correspondence to: David J Hunter1,4,5,6,22 e-mail: dhunter@hsph.harvard.edu
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