Bethesda guidelines: Relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer

Background: Microsatellite instability is a hallmark of mismatch repair def iciency in hereditary nonpolyposis colorectal cancer and results from mutat ions in the mismatch repair genes MLH1 or MSH2 or from gene inactivation as sociated with DNA methylation. The Bethesda guidelines were established to identify patients with colorectal cancer who should be tested for microsate llite instability. Objective: To assess the Bethesda guidelines for detection, of microsatelli te instability and to determine the role of MLH1 promoter methylation in co lorectal cancer. Design: Prospective cohort study. Setting: Tertiary care referral center in Frankfurt, Germany. Patients: 125 consecutive patients with colorectal cancer. Measurements, Patients were assessed according to the Bethesda guidelines, and tumor specimens were analyzed for micro-satellite instability. Patients with microsatellite Instability were tested for MLH1 promoter methylation and MLH1 and MSH2 germline mutations. Results: Microsatellite instability w as detected in 17 of 58 patients who fulfilled and 5 of 67 patients who did not fulfill criteria of the Bethesda guidelines. In I I of 17 patients wit h microsatellite instability who fulfilled Bethesda guidelines, an MLH1 (n = 3), MSH2 (n = 7), or combined MLH1 and MSH2 (n = 1) mutation was found. A mong the patients with microsatellite instability who did not fulfill Bethe sda guidelines, no mutations were observed; MLH1 promoter methylation was o bserved in 6 of 11 patients with an MLH1 or MSH2 mutation and 5 of 11 patie nts without an MLH1 or MSH2 mutation. Conclusions: The Bethesda guidelines are useful for selecting patients for microsatellite instability testing. MLH1 and MSH2 testing should be recomme nded in all patients with colorectal cancer and microsatellite instability who fulfill at least one Bethesda criterion. MLH1 promoter methylation may accompany rather than initiate carcinogenesis in patients with colorectal c ancer who have mismatch repair gene defects.