The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer
The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer
复制标题
DOI：
10.1053/gast.2001.27996
复制
发表时间：
2001-10-01
期刊：
影响因子：
29.4
通讯作者：
Slattery, ML
中科院分区：
文献类型：
--
作者：
Samowitz, WS;Curtin, K;Slattery, ML
背景与目的：基于临床标准的遗传性非息肉病性结肠癌（HNPCC）发生率的估计差异很大。最近对生殖系错配修复基因突变的研究表明，HNPCC占所有结肠癌的近3%，但这一估计可能因包括芬兰特有的创始人效应而被夸大。因此，我们在一项对来自犹他州和加州的1066名个体进行的基于人群的研究中，通过遗传标准确定了与HNPCC相关的结肠癌负担。研究方法：错配修复基因hMSH 2和hMLH 1的编码区从那些肿瘤表现出微卫星不稳定性的个体的种系中测序。结果：16%（171/1066）的肿瘤存在微卫星不稳定性。致病性生殖系错配修复基因突变被确定在7个人，和错义氨基酸的变化不确定的意义在另外6个人。在调整足够的生殖系DNA用于测序后，7个明显致病的突变占群体水平结肠癌的0.86%。与不稳定肿瘤但无生殖系突变的个体相比，具有这些突变的个体明显更年轻，更可能有结肠癌和子宫内膜癌的家族史，并且更可能有一级亲属在10岁时发生结肠癌（P < 0.01）。结论：我们的结论是，遗传定义的HNPCC占结肠癌的一个非常小的百分比在人口水平上，一个百分比低于大多数以前的临床研究估计。
Background & Aims: Estimates of the frequency of hereditary nonpolyposis colon cancer (HNPCC) based on clinical criteria have varied widely. Recent studies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have been inflated by inclusion of founder effects peculiar to Finland. We therefore determined by genetic criteria the colon cancer burden associated with HNPCC in a population-based study of 1066 individuals from Utah and California. Methods: The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability. Results: Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene mutations were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adjusting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the population level. Individuals with these mutations were significantly younger, more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young-age onset of colon cancer than individuals with unstable tumors but without germline mutations (P < 0.01). Conclusions: We conclude that genetically defined HNPCC accounts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies.