Pande Mala, Chen Jinyun, Amos Christopher I, Lynch Patrick M, Broaddus Russell, Frazier Marsha L
Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1155 Hermann P. Pressler Boulevard, Houston, TX 77030, USA.
Cancer Epidemiol Biomarkers Prev. 2007 Sep;16(9):1753-9. doi: 10.1158/1055-9965.EPI-07-0384.
Lynch syndrome is caused by germ-line mutations in the DNA mismatch repair (MMR) genes; mutation carriers are predisposed to a variety of cancers, most commonly colorectal and endometrial. The median age of colorectal cancer onset is 45 years and the lifetime risk is approximately 80%, but the onset age varies substantially. It is likely that other low-penetrance genes and environmental factors act as modifiers of the risk associated with the highly penetrant MMR gene mutations. Methylenetetrahydrofolate reductase plays a key role in folate metabolism. We investigated the association of C677T and A1298C, two common polymorphisms in the methylenetetrahydrofolate reductase gene, with risk for early onset colorectal cancer in Lynch syndrome. Subjects were 185 non-Hispanic whites with confirmed DNA MMR mutations. Kaplan-Meier estimates for the age at colorectal cancer onset according to C677T genotypes were significantly different for the CT and TT genotypes compared with the wild-type CC (P = 0.014, log-rank test; P = 0.004, trend test). The median ages at onset were 39 [corrected] years for the CC genotype and 43 [corrected] years for the combined CT and TT [corrected] genotypes and the CT+TT [corrected] genotypes were associated with a reduced age-associated risk for developing colorectal cancer (hazard ratio, 0.55; 95% confidence interval, 0.36-0.85). No differences in ages at onset or risk were found for the A1298C genotypes. This is the first report to our knowledge to provide evidence that the C677T polymorphism modifies the age at onset of colorectal cancer in Caucasian Lynch syndrome subjects with the 677T allele having a protective effect.
林奇综合征由DNA错配修复（MMR）基因的种系突变引起；突变携带者易患多种癌症，最常见的是结直肠癌和子宫内膜癌。结直肠癌发病的中位年龄为45岁，终生风险约为80%，但发病年龄差异很大。其他低 penetrance 基因和环境因素可能作为与高 penetrance MMR 基因突变相关风险的修饰因子。亚甲基四氢叶酸还原酶在叶酸代谢中起关键作用。我们研究了亚甲基四氢叶酸还原酶基因中两个常见多态性C677T和A1298C与林奇综合征患者早发性结直肠癌风险的关联。研究对象为185名确诊有DNA MMR突变的非西班牙裔白人。根据C677T基因型对结直肠癌发病年龄的Kaplan-Meier估计显示，与野生型CC相比，CT和TT基因型有显著差异（P = 0.014，对数秩检验；P = 0.004，趋势检验）。CC基因型的发病中位年龄为39[校正]岁，CT和TT合并[校正]基因型的发病中位年龄为43[校正]岁，CT+TT[校正]基因型与结直肠癌发病的年龄相关风险降低有关（风险比，0.55；95%置信区间，0.36 - 0.85）。A1298C基因型在发病年龄或风险方面未发现差异。据我们所知，这是第一份提供证据表明C677T多态性改变了白种人林奇综合征患者结直肠癌发病年龄，且677T等位基因具有保护作用的报告。
