MLH1-93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer
MLH1-93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer
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DOI：
10.1093/jnci/djk095
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发表时间：
2007-03-21
影响因子：
10.3
通讯作者：
Bapat, Bharati
中科院分区：
文献类型：
--
作者：
Raptis, Stavroula;Mrkonjic, Miralem;Bapat, Bharati
背景：虽然高达30%的结直肠癌患者有阳性的结直肠癌肿瘤家族史，但很少有结直肠癌可以通过高外显率基因突变来解释。我们研究了DNA错配修复基因的多态性是否与结直肠癌的风险相关。方法采用荧光5′核酸酶法对来自安大略省的929例患者和1098例对照者以及来自纽芬兰和拉布拉多的430例患者和275例对照者进行错配修复基因MLH1和MSH2的5个多态性进行基因分型。采用聚合酶链反应法测定肿瘤微卫星不稳定性（MSI）；MSI状态分为高（MSI- h, >=所有标记物中30%不稳定标记物）、低（MSI- l, < 30%标记物不稳定）或稳定（MSS，没有不稳定标记物）。在调整年龄和性别后，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系。用Pearson卡方检验或Fisher精确检验来评估多态性与肿瘤临床病理特征之间的关系。所有统计检验均为双侧检验。结果在安大略省（P= 0.001）和纽芬兰省（P= 0.003）的患者中，MLH1 -93G > A多态性与MSI-H肿瘤有很强的相关性。与对照人群相比，安大略省（校正优势比[OR] = 3.23, 95%可信区间[CI] = 1.65至6.30）和纽芬兰（OR 8.88, 95% Cl = 2.33至33.9）的病例患者中MLH1 -93G >变异等位基因的纯合度与IVISI-H肿瘤相关，安大略省（OR = 1.84, 95% Cl = 1.20至2.83）和纽芬兰（OR = 2.56, 95% Cl = 1.14至5.75）的病例患者的杂合度也与IVISI-H肿瘤相关。MSS患者和MSI-L肿瘤患者与对照组的基因型频率相似，纯合子变异携带者多数存在MSS肿瘤。在来自安大略省的病例患者中，MLH1-93G > A多态性与结直肠癌家族史之间存在关联（对于阿姆斯特丹标准I和II， P = 0.004和P = 0.02）。结论在两个患者群体中，MLH1-93G > A多态性与IVISI-H结直肠癌的风险增加有关。
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, >= 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 IVISI-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% Cl = 2.33 to 33.9), as was heterozygosity among case patients in Ontario (OR = 1.84, 95% Cl 1.20 to 2.83) and in Newfoundland (OR = 2.56, 95% Cl = 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 IVISI-H colorectal cancer.