Human Molecular Genetics Advance Access originally published online on August 18, 2004
Human Molecular Genetics 2004 13(20):2431-2441; doi:10.1093/hmg/ddh270
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Human Molecular Genetics, Vol. 13, No. 20 © Oxford University Press 2004; all rights reserved
Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic Cohort
1The Broad Institute of MIT and Harvard, Cambridge, MA, USA, 2Department of Medicine, 3Department of Molecular Biology, 4Department of Hematology/Oncology and 5Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA, 6Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, 7Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, USA and 8Divisions of Genetics and 9Division of Endocrinology, Children's Hospital, Boston, MA, USA and 10Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Received May 28, 2004; Revised August 11, 2004;
It is well established that rare mutations in BRCA2 predispose to familial breast cancer, but whether common variants at this locus contribute more modest risk to sporadic breast cancer has not been thoroughly investigated. We performed a haplotype-based study of BRCA2 among women in the Multiethnic Cohort Study (MEC), genotyping 50 SNPs spanning 109.4 kb of the BRCA2 gene. Twenty-one haplotype-tagging SNPs (including seven missense SNPs) were selected to predict the common BRCA2 haplotypes and were genotyped in a breast cancer case–control study nested in the MEC (cases, n=1715; controls, n=2502). Compared to non-carriers, we observed nominally significant positive associations for homozygous carriers of specific haplotypes in blocks 2 (haplotype 2c: OR=1.50; 95% CI, 1.08–2.09) and 3 (haplotype 3d: OR=1.50; 95% CI, 1.01–2.24). These results could be explained on the basis of a single marker in intron 24 (SNP 42: rs206340) that was correlated with these haplotypes and the homozygous state was associated with a significantly increased risk of breast cancer (AA versus GG genotypes: OR=1.59, 95% CI, 1.18–2.16; nominal P=0.005). This association was modestly stronger among women with advanced disease (OR=2.00, 95% CI, 1.30–3.08; P=0.002). In this exploratory analysis, we found little indication that common variation in BRCA2 dramatically impacts sporadic breast cancer risk. However, a significant elevation in risk was observed among 
6% of women who carried a specific haplotype pattern and may harbor a susceptibility allele at the BRCA2 locus.
* To whom correspondence should be addressed at: Department of Preventive Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Rm 4441, Los Angeles, CA 90089-9175, USA. Tel: +1 3238650429; Fax: +1 3238650127; Email: haiman{at}usc.edu
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