Age-related hypermethylation of the 5 ' region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development

Hypermethylation of the MLH1 promoter underlies most sporadic colorectal ca ncers with microsatellite instability (MSI). To investigate the role of hyp ermethylation in the normal colonic mucosa as a possible precursor lesion, we studied 700 bp upstream of MLH1 covering 51 CpG sites. We found partiall y methylated alleles in 15 of 34 (44%) patients <60 years of age and 20 of 24 (83%) patients <greater than or equal to>80 years of age (P = 0.0026). F ully methylated alleles were present in 18 of 33 (55%) patients with MSI+ t umors but in only 18 of 90 (20%) patients with MSI- tumors (P = 0.00019). B y in situ analysis, methylation was patchy and located mainly in the crypta l regions close to the lumen. We conclude that the spread of methylation in the MLH1 promoter in the normal colonic mucosa is closely associated with age and the development of sporadic MSI+ colorectal cancers.