Microsatellite instability in colitis associated colorectal cancer

Microsatellite instability in colitis associated colorectal cancer As molecular pathways of colon carcinogenesis continue to be defined for high risk hereditary colon cancer syndromes and for average risk sporadic colon cancers, it seems that colon carcinogenesis in the setting of chronic idiopathic inflammatory bowel disease (IBD) may be unique. 1 Although to some extent this notion seems intuitive because of the substrate of chronic inflammation from which these cancers arise, it is nevertheless curious that despite the setting of chronic inflammation, colon cancers occurring in patients with colitis share several features in common with those that arise in patients with hereditary non-polyposis colorectal cancer (HNPCC). For example, in both conditions there is a tendency for the colorectal cancers to aVect young individuals, be multifocal, show a proximal colonic distribution, and display mucinous, signet-ring cell or undiVerentiated histology. In addition, HNPCC colorectal cancers often have a rim of surrounding inflammation, referred to as a Crohn's-like reaction. These clinicopathological similarities have prompted some investigators to explore whether colitis associated cancers might in fact share a common molecular pathogenesis with HNPCC colorectal cancers. Colorectal cancers in patients with HNPCC occur by virtue of a defective ability to repair DNA base pair mismatches. This results in DNA replication errors that have the net eVect of altering genes that are critical for maintaining normal growth and behaviour of colonic epithelial cells. Such replication errors can be identified using markers that detect short repetitive sequences, or microsatellites, located throughout the genome. Errors in replicating these sequences result in a phenotype termed microsatellite instability (MI). Several genes act in concert to orchestrate normal repair of DNA base mismatches, including hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2. 2 Except for hMSH3, germline mutations of any one of these genes are known to give rise to tumours of the colorectum and other organs in patients with HNPCC, with mutations of hMLH1 and hMSH2 accounting for the vast majority of known HNPCC families. In this issue (see page 367), Cawkwell and colleagues investigated the frequency of MI in colitis associated color-ectal cancers to determine whether these tumours might share a similar molecular pathogenesis with HNPCC. They analysed 46 colitis associated colonic adenocarcino-mas for MI using a panel of four markers in a fluorescence PCR-based MI assay, and also stained tumours by using immunohistochemistry for loss of hMLH1 and hMSH2. Six (15%) of 41 cases demonstrated MI at one or more …