Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic Cohort.
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 approximately 6% of women who carried a specific haplotype pattern and may harbor a susceptibility allele at the BRCA2 locus.
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Matthew L
ML
Freedman
Kathryn L
KL
Penney
Daniel O
DO
Stram
Loïc
L
Le Marchand
Joel N
JN
Hirschhorn
Laurence N
LN
Kolonel
David
D
Altshuler
Brian E
BE
Henderson
Christopher A
CA
Haiman
D000368:Aged; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors