Microsatellite instability and K-ras mutations in patients with ulcerativecolitis

Patients with inflammatory bowel disease (IBD), particularly ulcerative col itis (UC), have an increased incidence of colorectal carcinoma. The underly ing mechanism is unknown, but we postulated that microsatellite instability (MSI) might predispose the colonic mucosa of UC patients to mutations, the reby increasing their cancer risk. We also sought to determine the frequenc y of K-ras mutations, to determine whether MSI predisposed to K-ras mutatio ns and to compare the molecular phenotype of biopsy and resection specimens in the same patient. We also sought to determine whether molecular alterat ions found in biopsy specimens presaged their presence in subsequent resect ion specimens. Two hundred fifty-eight specimens from 52 patients were exam ined for K-ras mutations by direct sequencing. Seventy-one of the specimens were neoplastic. MSI was evaluated after polymerase chain reaction (PCR) a mplification using primers directed at 8 microsatellite loci. Of the patien ts, 18.2% had K-ras mutations, and 30.8% had MSI in at least 1 locus. Of K- ras mutations, 81.8% were G to A substitutions involving the second nucleot ide of codons 12 or 13. Only 0.7% of the samples showed a high level of MSI . No relationship existed between MSI and K-ras mutations, even in the 2 sa mples with high-level MSI. The numbers are small, but it appeared that MSI in biopsies failed to predict its presence in resection specimens. In contr ast, K-ras mutations present in biopsy specimens tended to predict their pr esence in resections. K-ras mutations were found predominantly in neoplasti c mucosae, whereas MSI was found predominantly in regenerative mucosae. The lack of any relationship between MSI and K-ras mutations suggests that MSI in the UC replicative mucosa does not predispose to colonic neoplasia via a K-ras-mediated pathway. This is probably related to the fact that the MSI is generally low-level MSI. HUM PATHOL 31:665-671. Copyright (C) 2000 by W .B. Saunders Company.