Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer.
Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer.
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发表时间：
1996-06
期刊：
影响因子：
8
通讯作者：
V. Bubb;L. Curtis;C. Cunningham;M. Dunlop;A. Carothers;R. Morris;Susan White;Bird Cc;A. Wyllie
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作者：
V. Bubb;L. Curtis;C. Cunningham;M. Dunlop;A. Carothers;R. Morris;Susan White;Bird Cc;A. Wyllie
微卫星不稳定性（MSI）发生在遗传性非息肉病性结直肠癌（HNPCC）患者的大多数肿瘤中，约17%的散发性结直肠癌中。错配修复（MMR）基因的种系缺陷是大多数大型HNPCC家族的原因，其中hMSH 2至少占50%。MMR基因缺陷也发生在一小部分散发性结直肠肿瘤MSI。在这里，我们报告了215例散发性结直肠肿瘤苏格兰患者的错配修复缺陷的系统分析。我们发现，16.4%的肿瘤表现出MSI;生存分析的考克斯比例风险法显示出一个实质性的生存优势，肿瘤显示MSI，独立于其他预后因素。对MSI肿瘤进行hMSH 2突变筛查，尽管发现61%有改变，但其中只有1/24是外显子突变。这些变化中的大多数是在内含子monoclantide tracts的长度减少，我们假设这些改变是其他地方的遗传缺陷的结果，虽然它们可能会损害hMSH 2功能作为肿瘤发生的第二步。我们的研究结果表明，不稳定性改善了结直肠癌的预后，尽管这两组肿瘤具有相似的生物学特征，但HNPCC和散发性结直肠癌MSI的遗传基础是不同的。
Microsatellite instability (MSI) occurs in most tumours from patients with hereditary non-polyposis colorectal cancer (HNPCC) and in around 17% of sporadic colorectal cancers. Germline defects in mismatch repair (MMR) genes are responsible for the majority of large HNPCC families, with hMSH2 accounting for at least 50%. MMR gene defects also occur in a small proportion of sporadic colorectal tumours with MSI. Here we report a systematic analysis of mismatch repair deficiency in 215 Scottish patients with sporadic colorectal tumours. We found that 16.4% of tumours exhibited MSI; survival analysis by Cox proportional hazards method showed a substantial survival advantage for patients with tumours showing MSI, independent of other prognostic factors. Tumours with MSI were screened for hMSH2 mutations and although 61% were found to have alterations, of these only 1/24 was exonic. The majority of these changes were reductions in length at intronic mononucleotide tracts and we postulate that these alterations are the result of a genetic defect elsewhere, although they may compromise hMSH2 function as a second step in tumourigenesis. Our findings indicate that instability confers an improved prognosis in colorectal cancer and, despite the fact that these two groups of tumours share similar biological characteristics, the genetic basis of HNPCC and sporadic colorectal cancer with MSI is different.