Barnetson R, Jass J, Tse R, Eckstein R, Robinson B, Schnitzler M
Department of Cancer Genetics, Kolling Institute, Royal North Shore Hospital, St. Leonard's, University of Sydney, Australia.
Genes Chromosomes Cancer. 2000 Oct;29(2):130-6. doi: 10.1002/1098-2264(200010)29:2<130::aid-gcc1023>3.0.co;2-z.
Although microsatellite instability (MSI) has been shown to be present in 15% of sporadic colorectal carcinomas, the genetic events underlying the development of these tumors have not been well described. By investigating intratumoral heterogeneity, this study attempts to elucidate whether MSI-positive colorectal carcinomas develop as the result of a random accumulation of mutations or as an ordered, stepwise sequence of genetic alterations. Eighty-six regions from 16 MSI-positive sporadic colorectal carcinomas were examined for mutations in repeat nucleotide sequences of the tumour suppressor genes transforming growth factor beta type II receptor (TGFBRII), insulin-like growth factor II receptor (IGFIIR), and BAX, and the mismatch repair genes MSH3 and MSH6. At least 2 and up to 5 of these genes were mutated in each tumour, and widespread intratumoral heterogeneity was observed for each gene. Regions of tumour with TGFBRII mutations were correlated with a poorly differentiated histology. Unlike the situation in microsatellite stable colorectal carcinomas, the findings of the present study did not suggest that a particular sequence of tumour suppressor and mismatch repair genes are mutated during colorectal tumorigenesis. It seems likely that a random accumulation of mutations, as a result of a defect in the mismatch repair pathway, drives tumour progression in this type of colorectal carcinoma.
尽管微卫星不稳定性（MSI）已被证实在15%的散发性结直肠癌中存在，但这些肿瘤发生发展的潜在遗传事件尚未得到充分描述。通过研究肿瘤内异质性，本研究试图阐明MSI阳性的结直肠癌是由于随机的突变积累，还是作为一种有序的、逐步的遗传改变序列而发生发展的。对16例MSI阳性散发性结直肠癌的86个区域进行检测，以查找肿瘤抑制基因转化生长因子βII型受体（TGFBRII）、胰岛素样生长因子II受体（IGFIIR）和BAX以及错配修复基因MSH3和MSH6的重复核苷酸序列中的突变。每个肿瘤中至少有2个且多达5个这些基因发生了突变，并且观察到每个基因都存在广泛的肿瘤内异质性。具有TGFBRII突变的肿瘤区域与低分化组织学相关。与微卫星稳定的结直肠癌情况不同，本研究结果并未表明在结直肠癌发生过程中，肿瘤抑制基因和错配修复基因存在特定的突变顺序。似乎由于错配修复途径缺陷导致的随机突变积累驱动了这类结直肠癌的肿瘤进展。
