Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

Abstract

Summary 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.

MSI-L Gastric Carcinomas Share the hMLH1 Methylation Status of MSI-H Carcinomas but Not Their Clinicopathological Profile

“…We detected an aberrant hMLH1 promoter methylation in 75% of MSI-H gastric carcinoma cases leading to the absence or diminished expression of hMLH1. This percentage fits with those previously reported for SGC (Fleisher et al, 1999;Kang et al, 1999;Leung et al, 1999;Toyota et al, 1999;Wu et al, 2000;Yamamoto et al, 1999), sporadic colorectal carcinomas (Cunningham et al, 1998;Ghimenti et al, 1999;Kang et al, 1999), and endometrial carcinomas displaying MSI (Esteller et al, 1998;Simpkins et al, 1999). The RT-PCR analysis of hMLH1 expression showed that there is a significant association between hMLH1 hypermethylation and loss of hMLH1 expression as previously reported by Deng et al (1999).…”

Allelic loss and gain, but not genomic instability, as the major somatic mutation in primary hepatocellular carcinoma

“…The presence of novel fragments in amplified products of cancer DNAs compared with those of reference DNAs is a strong indicator of genomic instability. Frequent MSI has been reported in colorectal carcinoma and some other solid tumors (Ghimenti et al, 1999). There were controversies in previous reports with regard to the incidence of MSI in HCC (Salvucci et al, 1999;Sheu et al, 1999).…”

Medical Management of Pancreatic Adenocarcinoma

“…There may also be an increase in risk for those with familial adenomatous polyposis [19] and Lynch syndrome II [29] . Conflicting data are available about the increased relative risk related to diet [30,31] (high intake of fat and meat), coffee and alcohol consumption [32,33] , aspirin and NSAID use [34][35][36] , past partial gastrectomy [37] or cholecystectomy [38] .…”

“…These genes are related to hereditary non-polyposis colorectal cancer (HNPCC), and loss of their function can justify the increased risk of pancreatic cancer in families with a history of HNPCC [19] .…”