Koessler T, Oestergaard M Z, Song H, Tyrer J, Perkins B, Dunning A M, Easton D F, Pharoah P D P
Cancer Research UK Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Worts Causeway, Cambridge, UK.
Gut. 2008 Aug;57(8):1097-101. doi: 10.1136/gut.2007.137265. Epub 2008 Mar 25.
The mismatch repair (MMR) genes are in charge of maintaining genomic integrity. Mutations in the MMR genes are at the origin of a familial form of colorectal cancer (CRC). This syndrome accounts for only a small proportion of the excess familial risk of CRC. The characteristics of the alleles that account for the remainder of cases are unknown. To assess the putative associations between common variants in MMR genes and CRC, we performed a genetic case-control study using a single-nucleotide polymorphism (SNP) tagging approach.
A total of 2299 cases and 2284 unrelated controls were genotyped for 68 tagging SNPs in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were measured in cases and controls and analysed using univariate analysis. Haplotypes were constructed and analysed using logistic regression. We also carried out a two-locus interaction analysis and a global test analysis.
Genotype frequencies were found to be marginally different in cases and controls for MSH3 rs26279 with a rare homozygote OR = 1.31 [95% confidence interval (CI) 1.05 to 1.62], p(trend) = 0.04. We found a rare MLH1 (frequency <5%) haplotype, increasing the risk of colorectal cancer: (OR = 9.76; 95% CI, 1.25 to 76.29; p = 0.03). The two-locus interaction analysis has exhibited signs of interaction between SNPs located in genes MSH6 and MSH2. Global testing has showed no evidence of interaction.
It is unlikely that common variants in MMR genes contribute significantly to colorectal cancer.
错配修复（MMR）基因负责维持基因组完整性。MMR基因突变是家族性结直肠癌（CRC）的病因。该综合征仅占CRC家族性额外风险的一小部分。导致其余病例的等位基因特征尚不清楚。为了评估MMR基因常见变异与CRC之间的假定关联，我们采用单核苷酸多态性（SNP）标签法进行了一项遗传病例对照研究。
对2299例患者和2284例无关对照进行了7个MMR基因（MLH1、MLH3、MSH2、MSH3、MSH6、PMS1和PMS2）中68个标签SNP的基因分型。测量病例组和对照组的基因型频率，并使用单变量分析进行分析。构建单倍型并使用逻辑回归进行分析。我们还进行了两位点相互作用分析和全局检验分析。
发现MSH3 rs26279在病例组和对照组中的基因型频率略有不同，罕见纯合子的比值比（OR）=1.31 [95%置信区间（CI）1.05至1.62]，p（趋势）=0.04。我们发现一种罕见的MLH1（频率<5%）单倍型，增加了结直肠癌风险：（OR = 9.76；95% CI，1.25至76.29；p = 0.03）。两位点相互作用分析显示位于MSH6和MSH2基因中的SNP之间存在相互作用迹象。全局检验未显示相互作用的证据。
MMR基因的常见变异不太可能对结直肠癌有显著影响。
