Samowitz W S, Curtin K, Lin H H, Robertson M A, Schaffer D, Nichols M, Gruenthal K, Leppert M F, Slattery M L
Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.
Gastroenterology. 2001 Oct;121(4):830-8. doi: 10.1053/gast.2001.27996.
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.
The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability.
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).
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.
基于临床标准对遗传性非息肉病性结直肠癌（HNPCC）发病率的估计差异很大。近期对种系错配修复基因突变的研究表明，HNPCC约占所有结直肠癌的3%，但这一估计可能因纳入了芬兰特有的奠基者效应而被高估。因此，我们在一项对来自犹他州和加利福尼亚州的1066名个体的人群研究中，通过基因标准确定了与HNPCC相关的结直肠癌负担。
对肿瘤表现出微卫星不稳定性的个体的种系进行错配修复基因hMSH2和hMLH1编码区测序。
16%（171/1066）的肿瘤存在微卫星不稳定性。在7名个体中鉴定出致病性种系错配修复基因突变，在另外6名个体中鉴定出意义不确定的错义氨基酸变化。在调整了有足够种系DNA用于测序的情况后，7个明确的致病性突变在人群水平上占结直肠癌的0.86%。与肿瘤不稳定但无种系突变的个体相比，有这些突变的个体显著更年轻，更可能有结直肠癌和子宫内膜癌家族史，且更可能有结直肠癌发病年龄较轻的一级亲属（P < 0.01）。
我们得出结论，在人群水平上，基因定义的HNPCC在结直肠癌中所占比例非常小，低于大多数先前临床研究的估计。
