Jones J Shawn, Amos Christopher I, Pande Mala, Gu Xiangjun, Chen Jinyun, Campos Imelda M, Wei Qingyi, Rodriguez-Bigas Miguel, Lynch Patrick M, Frazier Marsha L
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Unit 189, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):886-91. doi: 10.1158/1055-9965.EPI-05-0644.
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies resulting from germ-line mutations in DNA mismatch repair genes. Colorectal and endometrial cancers are most frequently observed. A polymorphic C-to-T change in the promoter region of the DNMT3b gene, -149 bp from the transcription start site, is reported to greatly increase promoter activity and is associated with increased risk for lung cancer and decreased postsurgical survival in patients with small cell carcinoma of the head and neck. We studied the influence of this DNMT3b polymorphism on HNPCC age of onset. We determined the DNMT3b genotype of 146 mismatch repair mutation carriers from 72 families. Of these, 74 participants had colorectal cancer. The participants were genotyped by single-strand conformational polymorphism analysis and DNA sequencing. We tested the association between age of onset and DNMT3b genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test, Wilcoxon's test, and Fleming-Harrington test and estimating the strength and direction of the association using the Cox proportional hazards regression model adjusting for potential demographic and genetic confounding factors. HNPCC patients carrying one or two copies of the DNMT3b variant T allele developed their colorectal cancer significantly earlier than HNPCC patients who were homozygous for the wild-type DNMT3b allele. Combining knowledge of an individual's DNMT3b genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.
遗传性非息肉病性结直肠癌（HNPCC）是一种常染色体显性遗传的家族性恶性肿瘤综合征，由DNA错配修复基因的种系突变引起。结直肠癌和子宫内膜癌最为常见。据报道，DNMT3b基因启动子区域（转录起始位点上游149 bp处）的一个多态性C到T的变化会显著增加启动子活性，并且与肺癌风险增加以及头颈部小细胞癌患者术后生存率降低有关。我们研究了这种DNMT3b多态性对HNPCC发病年龄的影响。我们确定了来自72个家庭的146名错配修复突变携带者的DNMT3b基因型。其中，74名参与者患有结直肠癌。通过单链构象多态性分析和DNA测序对参与者进行基因分型。我们通过比较Kaplan-Meier生存曲线来测试发病年龄与DNMT3b基因型之间的关联，使用对数秩检验、Wilcoxon检验和Fleming-Harrington检验评估曲线的同质性，并使用Cox比例风险回归模型估计关联的强度和方向，同时对潜在的人口统计学和遗传混杂因素进行调整。携带一个或两个拷贝的DNMT3b变异T等位基因的HNPCC患者患结直肠癌的时间明显早于野生型DNMT3b等位基因纯合的HNPCC患者。将个体的DNMT3b基因型知识与其他遗传和环境风险因素信息相结合，可能会改善风险评估，并有助于识别在较年轻时对HNPCC具有遗传易感性的个体。
