Wang W W, Spurdle A B, Kolachana P, Bove B, Modan B, Ebbers S M, Suthers G, Tucker M A, Kaufman D J, Doody M M, Tarone R E, Daly M, Levavi H, Pierce H, Chetrit A, Yechezkel G H, Chenevix-Trench G, Offit K, Godwin A K, Struewing J P
Laboratory of Population Genetics, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Cancer Epidemiol Biomarkers Prev. 2001 Sep;10(9):955-60.
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.
RAD51与BRCA1和BRCA2均共定位，RAD51中的基因变异可能是BRCA1/2修饰因子的候选对象。我们通过对20名个体进行测序来寻找RAD51多态性。我们比较了携带或未携带乳腺癌或卵巢癌的女性BRCA1/2突变携带者之间以及基于人群的携带BRCA1/2突变的卵巢癌病例与未携带突变的病例及对照之间的多态性等位基因频率。我们在5'非翻译区的第135位（g→c）和第172位（g→t）发现了两个单核苷酸多态性（SNP）。在最初一组BRCA1/2突变携带者中，67例乳腺癌病例中有14例（21%）在RAD51的135位（g→c）携带“c”等位基因，而119名无乳腺癌的女性中有8例（7%）携带该等位基因。在来自三个中心的第二组466名突变携带者中，未证实RAD51的135位（g→c）与乳腺癌风险之间存在关联。然而，仅对216名BRCA2突变携带者进行分析时，发现135位的“c”等位基因与乳腺癌风险之间存在统计学上的显著关联（调整后的优势比为3.2；95%置信区间为1.4 - 4.0）。患有卵巢癌的BRCA1/2突变携带者携带RAD51的135位（g→c）SNP的可能性仅为一半左右。在一项来自以色列卵巢癌病例对照研究的738名受试者中对RAD51的135位（g→c）SNP进行分析，结果与携带“c”等位基因的BRCA1/2突变携带者患卵巢癌风险较低一致。我们已经鉴定出一个RAD51 5'非翻译区SNP，它可能与BRCA2突变携带者患乳腺癌风险增加以及患卵巢癌风险降低有关。这种风险修饰因子的生化基础目前尚不清楚。
