Department of Preventive Medicine, Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Cancer Prev Res (Phila). 2012 Feb;5(2):328-35. doi: 10.1158/1940-6207.CAPR-11-0419. Epub 2011 Dec 5.
Methylation of the MLH1 gene promoter region is an underlying cause of colorectal cancer (CRC) with high microsatellite instability (MSI-H) diagnosed in persons without a germ line mutation in a mismatch repair (MMR) gene (non-Lynch Syndrome CRC). It is unclear whether relatives of CRC cases with MLH1 methylation have an increased risk of colorectal or other cancers. In this retrospective cohort study, we assessed risk of CRC and other cancers for the first- and second-degree relatives of CRC cases with a methylated MLH1 gene, by comparing observed numbers of cases with those expected on the basis of age-, sex-, and country-specific cancer incidences (standardized incidence ratios). The cohort consisted of 3,128 first- and second-degree relatives of the 233 MLH1-methylated CRC cases with no MMR or MUTYH gene mutations. The standardized incidence ratio (SIR) for CRC was 1.60 [95% confidence interval (CI), 1.22-2.16] for first-degree relatives and 1.08 (0.74-1.60) for second-degree relatives. The SIR for gastric cancer was 2.58 (1.52-4.71) for first-degree relatives and 4.52 (2.23-10.61) for second-degree relatives and, for ovarian cancer, it was 2.16 (1.29-3.86) for first-degree relatives. The risk of liver cancer was also increased significantly in first-degree relatives but the estimate was on the basis of only two cases. These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non-Lynch syndrome CRCs.
MLH1 基因启动子区域的甲基化是一种潜在的原因，导致在没有错配修复（MMR）基因突变的情况下，诊断出具有高微卫星不稳定性（MSI-H）的结直肠癌（CRC）（非林奇综合征 CRC）。目前尚不清楚 MLH1 甲基化的 CRC 病例的亲属是否会增加结直肠或其他癌症的风险。在这项回顾性队列研究中，我们通过比较观察到的病例数与基于年龄、性别和国家特定癌症发病率（标准化发病比）预期的病例数，评估了 MLH1 基因甲基化的 CRC 病例的一级和二级亲属患 CRC 和其他癌症的风险。该队列由 233 例 MLH1 甲基化的 CRC 病例且无 MMR 或 MUTYH 基因突变的一级和二级亲属组成，共 3128 人。一级亲属的 CRC 标准化发病比（SIR）为 1.60（95%置信区间[CI]，1.22-2.16），二级亲属为 1.08（0.74-1.60）。一级亲属的胃癌 SIR 为 2.58（1.52-4.71），二级亲属为 4.52（2.23-10.61），而卵巢癌的 SIR 为 2.16（1.29-3.86）一级亲属。一级亲属的肝癌风险也显著增加，但该估计仅基于两例病例。这些数据表明，MLH1 甲基化的 CRC 病例的亲属可能会增加患 CRC 和胃癌的风险，并且可能会增加患卵巢癌和肝癌的风险，这表明在非林奇综合征 CRC 中，MLH1 甲基化相关的 CRC 和其他癌症可能存在遗传因素。
