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A Single Nucleotide Polymorphism in the 5' Untranslated Region of RAD51 and Risk of Cancer among BRCA1/2 Mutation Carriers¹

Laboratory of Population Genetics [W. W., S. M. E., D. J. K., J. P. S.], Genetic Epidemiology Branch [M. A. T.], Radiation Epidemiology Branch [M. M. D.], and Biostatistics Branch [R. E. T.], National Cancer Institute, NIH, Bethesda, Maryland 20892; Queensland Institute of Medical Research, Brisbane QLD 4029, Australia [A. B. S., G. C-T.]; South Australian Clinical Genetics Service, Adelaide 5005, Australia [G. S.]; Memorial Sloan Kettering Cancer Center, New York, New York 10021 [P. K., H. P., K. O.]; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [B. B., M. D., A. K. G.]; and Chaim Sheba Medical Center, Tel Hashomer, Israel 52641 [B. M., H. L., A. C., G. H. Y.]

RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 gc and 172 gt of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 gc, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 gc with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4–40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 gc SNP. Analysis of the RAD51:135 gc SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.

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