Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers

Microsatellite instability (MSI) is a hallmark of hereditary nonpolyposis c olorectal cancer, and in these patients, results from inherited defects in DNA mismatch repair genes, mostly MSH2 and MLH1. MSI also occurs in 15% of sporadic colorectal cancers, but in these tumors, its basis is less well ch aracterized. We investigated 46 sporadic MSI+ colorectal cancers for change s in MSH2 and MLH1 protein expression, followed by the analysis of somatic mutation, loss of heterozygosity (LOH), and promoter hypermethylation as po ssible underlying defects. Most cases (36/46, 78%) showed lost or reduced M LH1 expression. Among these, a majority (83%) was associated with MLH1 prom oter hypermethylation, whereas the rates of LOH and. somatic mutation of ML H1 were 24% and 13%, respectively. Hypermethylation and LOH were inversely correlated, suggesting that they had alternative functions in the inactivat ion of MLH1. MSH2 expression was lost in 7/46 (15%), and of these, 2 (29%) showed LOH and/or somatic mutation of MSH2, We conclude that most sporadic MSI+ colorectal cancers have an MLH1-associated etiology and that epigeneti c modification is a major mechanism of MI;HI inactivation. Moreover, we fou nd a significantly lower prevalence for MLH1 promoter hypermethylation in h ereditary nonpolyposis colorectal cancer tumors with MLH1 germline mutation s (12/26, 46%), which might explain some differences that are known to occu r in the clinicopathological characteristics and tumorigenic pathways betwe en sporadic and hereditary MSI+ colorectal cancers.