Common variants in mismatch repair genes and risk of invasive ovarian cancer
Common variants in mismatch repair genes and risk of invasive ovarian cancer
复制标题
DOI：
10.1093/carcin/bgl089
复制
发表时间：
2006-11-01
期刊：
影响因子：
4.7
通讯作者：
Gayther, Simon A.
中科院分区：
文献类型：
--
作者：
Song, Honglin;Ramus, Susan J.;Gayther, Simon A.
错配修复（MMR）是DNA复制过程中核苷酸错配修复的重要手段。MMR基因的种系突变与遗传性非息肉病性结直肠癌（HNPCC）有关。卵巢癌是HNPCC表型的一部分，因此MMR基因的常见变异是卵巢癌易感性的候选者。我们进行了一项大型多中心病例对照研究，使用单核苷酸多态性（SNP）标记方法调查MMR基因常见变异与卵巢癌的关系。对7个MMR基因（MLH1、MLH3、MSH2、MSH3、MSH6、PMS1和PMS2）中的44个标记snp （stSNP）进行了基因分型，共2570例对照和1531例病例。PMS2 rs7797466的基因型频率在病例和对照组之间差异不大（P-2df = 0.046），每个携带“a”等位基因的风险增加1.17倍（95% CI 1.03-1.33） （P-trend = 0.013）。PMS2的单倍型分析也显示病例和对照组之间的频率差异显著（P-7df = 0.005），其中一种单倍型占了大部分的影响。也有边际证据表明，普通纯合子作为两个snp的基线比较物，msh6 rs3136245 （OR 0.67; 95% CI 0.46-0.98）和MSH3 rs6151662 （OR 0.28; 95% CI 0.08-0.91）具有隐性保护作用，但这些变异的基因型频率比较不显著（P = 0.10和0.054）。总之，MLH1、MLH3、PMS1、MSH2、MSH3和MSH6的常见变异不太可能对卵巢癌易感性有显著影响。观察到的PMS2 rs7797466与卵巢癌的关联值得在一项独立研究中证实。
Mismatch repair (MMR) is important for repairing of nucleotide mismatches during DNA replication. Germline mutations in MMR genes are associated with hereditary non-polyposis colorectal cancer (HNPCC). Ovarian cancer occurs as part of the HNPCC phenotype, and so common variants in MMR genes are candidates for ovarian cancer susceptibility. We performed a large multicentre case-control study to investigate associations of common variations in MMR genes and ovarian cancer using a single nucleotide polymorphism (SNP) tagging approach. A total of 2570 controls and 1531 cases from three separate studies were genotyped for 44 tagging SNPs (stSNP) in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were marginally different between cases and controls for PMS2 rs7797466 (P-2df = 0.046) with a 1.17-fold (95% CI 1.03-1.33) increase in risk for each 'a' allele carried (P-trend = 0.013). Haplotype analysis of PMS2 also showed significant differences in frequencies between cases and controls (P-7df = 0.005), with one haplotype accounting for most of the effect. There was also marginal evidence for a recessive protective effect with common homozygote as the baseline comparator for two SNPs-MSH6 rs3136245 (OR 0.67; 95% CI 0.46-0.98) and MSH3 rs6151662 (OR 0.28; 95% CI 0.08-0.91)-but the comparisons of genotype frequencies for these variants were not significant (P = 0.10 and 0.054). In conclusion, it is unlikely that common variants in MLH1, MLH3, PMS1, MSH2, MSH3 and MSH6 contribute significantly to ovarian cancer susceptibility. The observed association of PMS2 rs7797466 with ovarian cancer warrants confirmation in an independent study.