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

• Published in: Cancer epidemiology, biomarkers & prevention biomarkers & prevention, 2001-09, Vol.10 (9), p.955-960
• Main Authors: WANG, Wendy W, SPURDLE, Amanda B, TARONE, Robert E, DALY, Mary, LEVAVI, Hanoch, PIERCE, Heather, CHETRIT, Angela, YECHEZKEL, Galit Hirsh, CHENEVIX-TRENCH, Georgia, OFFIT, Kenneth, GODWIN, Andrew K, STRUEWING, Jeffery P, KOLACHANA, Prema, BOVE, Betsy, MODAN, Baruch, EBBERS, Sarah M, SUTHERS, Graeme, TUCKER, Margaret A, KAUFMAN, David J, DOODY, Michele M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Australia; Biological and medical sciences; BRCA1 Protein - genetics; BRCA2 Protein; Breast Neoplasms - genetics; Case-Control Studies; DNA-Binding Proteins - genetics; Epidemiology; Female; Genetic Predisposition to Disease - genetics; Humans; Israel; Jews - genetics; Medical sciences; Middle Aged; Neoplasm Proteins - genetics; Ovarian Neoplasms - genetics; Polymorphism, Genetic; Rad51 Recombinase; Transcription Factors - genetics; Tumors; United States
• ISSN: 1055-9965; 1538-7755

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 g→c and 172 g→t 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 g→c, 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 g→c 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 g→c SNP. Analysis of the RAD51 :135 g→c 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.