Defective hMSH2/hMLH1 protein expression is seen infrequently in ulcerative colitis associated colorectal cancers

Abstract

Background-Ulcerative colitis is associated with an increased risk of colorectal cancer above that of the normal population. The relative risk correlates with the extent and duration of the disease but the genetic basis of ulcerative colitis associated cancer risk is not known. Aims-To assess the prevalence of microsatellite instability and mismatch repair gene abnormalities in ulcerative colitis associated colorectal cancer. Patients-Forty six patients with colorectal cancer, with a previous histological diagnosis of ulcerative colitis. Methods-The frequency of microsatellite instability and/or immunohistochemical expression of hMSH2 and hMLH1 was assessed. Thirty three cases were investigated using both approaches. Results-Although 6/41 (14.6%) cases showed microsatellite instability at one or more markers, only one case (2.4%) exhibited high level instability (at least two markers aVected). Of 38 cases which were assessed using antibodies against hMSH2 and hMLH1, only one case (2.6%) showed loss of expression. This case, which showed loss of hMSH2 expression, was the same case which exhibited high level microsatellite instability. The 33 cases which were investigated using both approaches showed that loss of expression of either hMSH2 or hMLH1 was not seen in any case which exhibited microsatellite instability in no more than one marker. Conclusions-This study suggests that both high level microsatellite instability and loss of expression of hMSH2/hMLH1 are infrequent events in ulcerative colitis associated colorectal cancers. Low level microsatellite instability was not associated with loss of expression of either hMSH2 or hMLH1.

The adaptive imbalance in base excision–repair enzymes generates microsatellite instability in chronic inflammation

“…One study reported 6 of 13 samples with high MSI as having hMLH1 hypermethylation (6). Unlike the findings in hereditary nonpolyposis colon cancer, however, other studies found little evidence for mismatch repair defects as a cause of MSI in UC (7,8). This raises the possibility that mechanisms other than mismatch repair defects exist.…”

Immunohistochemical analysis of adenocarcinoma of the small intestine: a tissue microarray study

“…27 However, it is only rarely involved in this setting: Cawkwell et al found neither MSI by PCR nor loss of hMLH1 and hMSH2 expression among 33 colorectal carcinomas complicating ulcerative colitis. 28 MSI also seems to be very unusual in cancers complicating Crohn's disease, even rarer than in those occurring in ulcerative colitis. 29 However, it should be noted that these studies only included colorectal carcinomas.…”

Genetics of inflammatory bowel disease and associated cancers

“…MSI tends to occur in a subset of about 10% to 15% of IBD tumors that retain their diploid chromosome number (ie, have a low level of CIN), and it was suggested that this subtype may exhibit a genetic predisposition towards MSI, perhaps as a consequence of mismatch repair gene mutation (an HNPCC variant) [41] or saturation as a consequence of increased oxidative stress [42]. Gene mutation is unlikely as low level MSI was not associated with any loss of expression of hMSH2 or hMLH1 protein in UC [43]. The frequency of MSI in acutely inflamed tissue suggests that mismatch repair mechanism saturation in inflammation is possible, but the low level of MSI compared with the high frequency of CIN seen in IBD-associated tumors suggests that MSI is not essential for carcinogenesis to occur in IBD.…”