Tulupova E, Kumar R, Hanova M, Slyskova J, Pardini B, Polakova V, Naccarati A, Vodickova L, Novotny J, Halamkova J, Hemminki K, Vodicka P
Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Mutat Res. 2008 Dec 15;648(1-2):40-5. doi: 10.1016/j.mrfmmm.2008.09.005. Epub 2008 Sep 21.
The Czech Republic presents one of the highest incidences of colorectal cancer in the world. We genotyped 10 single nucleotide polymorphisms in five DNA mismatch repair genes in 614 colorectal cancer cases and 614 matched controls from this country. The carriers of T-allele of the hMSH6-556G>T polymorphism were at increased risk of colorectal cancer (OR 1.29; 95% CI 1.02-1.62). The stratification of data showed that risk associated with the polymorphism was confined to rectal cancer (OR 1.42; 95% CI 1.03-1.95). The A-allele of the Ex1-145G>A polymorphism in the hMSH6 gene was associated with a decreased risk of colorectal cancer (OR 0.76; 95% CI 0.60-0.98). The C-allele of the IVS4-101G>C polymorphism in hMSH6 was associated with an increased risk of colon cancer (OR 1.34; 95% CI 1.03-1.74). The carriers of the variant allele for the polymorphism IVS9-1406C>T in hMLH1 exhibited a decreased risk of rectal cancer (OR 0.71; 95% CI 0.51-0.98). We observed a differential distribution of haplotypes based on three hMSH6 polymorphisms (-556G>T-Ex1-145G>A-IVS4-101G>C) in the cases and controls (global P=0.02). The TAG haplotype was associated with a decreased risk of colorectal cancer (OR 0.74; 95% CI 0.59-0.92), whereas the most frequent haplotype GGG was associated with increased risk of rectal cancer (OR 1.32; 95% CI 1.05-1.65). However, multiple hypotheses testing diminishes a statistical significance of above associations. Our data suggest a limited role for the investigated individual variants in mismatch repair genes for the susceptibility to the disease. The haplotypes covering hMSH6 gene may, however, be involved in risk modulation in this population.
捷克共和国是世界上结直肠癌发病率最高的国家之一。我们对该国614例结直肠癌病例和614例匹配对照的五个DNA错配修复基因中的10个单核苷酸多态性进行了基因分型。hMSH6基因-556G>T多态性的T等位基因携带者患结直肠癌的风险增加（比值比1.29；95%置信区间1.02 - 1.62）。数据分层显示，与该多态性相关的风险仅限于直肠癌（比值比1.42；95%置信区间1.03 - 1.95）。hMSH6基因Ex1-145G>A多态性的A等位基因与结直肠癌风险降低相关（比值比0.76；95%置信区间0.60 - 0.98）。hMSH6基因IVS4-101G>C多态性的C等位基因与结肠癌风险增加相关（比值比1.34；95%置信区间1.03 - 1.74）。hMLH1基因IVS9-1406C>T多态性的变异等位基因携带者患直肠癌的风险降低（比值比0.71；95%置信区间0.51 - 0.98）。我们观察到病例组和对照组中基于三个hMSH6多态性（-556G>T-Ex1-145G>A-IVS4-101G>C）的单倍型分布存在差异（总体P = 0.02）。TAG单倍型与结直肠癌风险降低相关（比值比0.74；95%置信区间0.59 - 0.92），而最常见的GGG单倍型与直肠癌风险增加相关（比值比1.32；95%置信区间1.05 - 1.65）。然而，多重假设检验降低了上述关联的统计学显著性。我们的数据表明，所研究的错配修复基因中的单个变异对该疾病易感性的作用有限。然而，覆盖hMSH6基因的单倍型可能参与了该人群的风险调节。
