Ghimenti C, Tannergård P, Wahlberg S, Liu T, Giulianotti P G, Mosca F, Fornaciari G, Bevilacqua G, Lindblom A, Caligo M A
Department of Oncology, University of Pisa, Italy.
Br J Cancer. 1999 Apr;80(1-2):11-6. doi: 10.1038/sj.bjc.6690314.
Genomic instability has been proposed as a new mechanism of carcinogenesis involved in hereditary non-polyposis colorectal cancer (HNPCC) and in a large number of sporadic cancers like pancreatic and colon tumours. Mutations in human mismatch repair genes have been found in HNPCC patients, but their involvement in sporadic cancer has not been clarified yet. In this study we screened 21 pancreatic and 23 colorectal sporadic cancers for microsatellite instability by ten and six different microsatellite markers respectively. Microsatellite alterations were observed at one or more loci in 66.6% (14/21) of pancreatic cancers and in 26% (6/23) colon tumours, but all the pancreatic and half of the colon samples showed a low rate of microsatellite instability. All the unstable samples were further analysed for mutations in the hMLH1 and hMSH2 genes and for hypermethylation of the hMLH1 promoter region. Alterations in the hMLH1 gene were found only in colorectal tumours with a large presence of microsatellite instability. None of the pancreatic tumours showed any alteration in the two genes analysed. Our results demonstrate that microsatellite instability is unlikely to play a role in the tumorigenesis of sporadic pancreatic cancers and confirm the presence of mismatch repair gene alterations only in sporadic colon tumours with a highly unstable phenotype.
基因组不稳定已被提出是一种致癌新机制，涉及遗传性非息肉病性结直肠癌（HNPCC）以及大量散发性癌症，如胰腺癌和结肠癌。在HNPCC患者中已发现人类错配修复基因的突变，但它们在散发性癌症中的作用尚未明确。在本研究中，我们分别用10个和6个不同的微卫星标记对21例胰腺散发性癌和23例结肠散发性癌进行微卫星不稳定性筛查。在66.6%（14/21）的胰腺癌和26%（6/23）的结肠癌肿瘤中，在一个或多个位点观察到微卫星改变，但所有胰腺样本和一半的结肠样本显示微卫星不稳定性发生率较低。对所有不稳定样本进一步分析hMLH1和hMSH2基因的突变以及hMLH1启动子区域的高甲基化。仅在微卫星不稳定性大量存在的结肠肿瘤中发现hMLH1基因改变。在所分析的两个基因中，未发现胰腺肿瘤有任何改变。我们的结果表明，微卫星不稳定性不太可能在散发性胰腺癌的肿瘤发生中起作用，并证实仅在具有高度不稳定表型的散发性结肠肿瘤中存在错配修复基因改变。
