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首页> 外文期刊>Journal of the National Cancer Institute >MLH1 -93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer.
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MLH1 -93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer.

机译：MLH1 -93G> A启动子多态性和微卫星不稳定结直肠癌的风险。

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BACKGROUND: Although up to 30% of patients with colorectal cancer have a positive family history of colorectal neoplasia, few colorectal cancers can be explained by mutations in high-penetrance genes. We investigated whether polymorphisms in DNA mismatch repair genes are associated with the risk of colorectal cancer. METHODS: We genotyped 929 case patients and 1098 control subjects from Ontario and 430 case patients and 275 control subjects from Newfoundland and Labrador for five polymorphisms in the mismatch repair genes MLH1 and MSH2 with the fluorogenic 5' nuclease assay. Tumor microsatellite instability (MSI) was determined with a polymerase chain reaction-based method; MSI status was assigned as high (MSI-H, > or = 30% unstable markers among all markers tested), low (MSI-L, <30% markers unstable), or stable (MSS, no unstable markers). We used unconditional logistic regression to evaluate the association between each polymorphism and colorectal cancer after adjusting for age and sex. The associations between polymorphisms and tumor clinicopathologic features were evaluated with a Pearson's chi-square or Fisher's exact test. All statistical tests were two-sided. RESULTS: We observed strong associations between the MLH1 -93G>A polymorphism and MSI-H tumors among case patients from Ontario (P = .001) and Newfoundland (P = .003). When compared with the control populations, homozygosity for the MLH1 -93G>A variant allele was associated with MSI-H tumors among case patients in Ontario (adjusted odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.65 to 6.30) and in Newfoundland (OR = 8.88, 95% CI = 2.33 to 33.9), as was heterozygosity among case patients in Ontario (OR = 1.84, 95% CI = 1.20 to 2.83) and in Newfoundland (OR = 2.56, 95% CI = 1.14 to 5.75). Genotype frequencies were similar among case patients with MSS and MSI-L tumors and control subjects, and the majority of homozygous variant carriers had MSS tumors. Among case patients from Ontario, an association between the MLH1 -93G>A polymorphism and a strong family history of colorectal cancer (for Amsterdam criteria I and II, P = .004 and P = .02, respectively) was observed. CONCLUSION: In two patient populations, the MLH1 -93G>A polymorphism was associated with an increased risk of MSI-H colorectal cancer.
机译：背景：尽管多达30％的大肠癌患者有大肠癌的阳性家族史，但很少有大肠癌可以通过高渗透性基因突变来解释。我们调查了DNA错配修复基因中的多态性是否与大肠癌的风险相关。方法：我们使用荧光5'核酸酶分析对错配修复基因MLH1和MSH2中的5个多态性进行了基因型分型，分别来自安大略省的929例患者和1098例对照受试者以及纽芬兰和拉布拉多的430例患者和275例对照受试者。用基于聚合酶链反应的方法测定肿瘤微卫星不稳定性（MSI）; MSI状态被指定为高（MSI-H，在所有测试标记中≥30％不稳定标记），低（MSI-L，<30％不稳定标记）或稳定（MSS，无不稳定标记）。在调整了年龄和性别之后，我们使用无条件逻辑回归来评估每种多态性与结直肠癌之间的关联。多态性与肿瘤临床病理特征之间的关联通过皮尔逊卡方检验或费舍尔精确检验进行评估。所有统计检验都是双面的。结果：我们在安大略省（P = .001）和纽芬兰（P = .003）的病例患者中观察到MLH1 -93G> A多态性与MSI-H肿瘤之间密切相关。与对照组相比，安大略省病例患者的MLH1-93G> A等位基因纯合性与MSI-H肿瘤相关（校正比值比[OR] = 3.23，95％置信区间[CI] = 1.65至6.30 ）和纽芬兰（OR = 8.88，95％CI = 2.33至33.9），安大略省（OR = 1.84，95％CI = 1.20至2.83）和纽芬兰（OR = 2.56，95％CI）病例患者之间的杂合性= 1.14至5.75）。在患有MSS和MSI-L肿瘤的病例患者与对照受试者之间，基因型频率相似，并且大多数纯合变异携带者患有MSS肿瘤。在安大略省的病例患者中，观察到MLH1-93G> A多态性与结直肠癌的家族史密切相关（对于阿姆斯特丹标准I和II，分别为P = .004和P = .02）。结论：在两个患者人群中，MLH1 -93G> A多态性与MSI-H大肠癌风险增加有关。

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