A single nucleotide substitution (-107C-->G) in the hMLH1 promoter found in colorectal cancer population reduces transcriptional activity.

Inactivation of the DNA mismatch repair gene hMLH1 predisposes one to colorectal cancer. We have identified a C to G nucleotide substitution at position -107 relative to the hMLH1 gene translation initiation site in three of 163 colorectal cancer patients with an allele frequency of 0.0092 (3/326). One of the three -107G alleles occurred in one patient out of five with reduced hMLH1 expression in the tumor tissue. The -107G was not found in 63 healthy individuals. This substitution reduced transcriptional activity by 51% compared with -107C (P<0.01) and impeded the promoter-binding capacity of nuclear proteins. Although the small number of identified -107G alleles is insufficient to evaluate the contribution to the carcinogenesis and clinicopathological properties of the tumors, the effects of -107G on hMLH1 gene transcription and nuclear protein binding to the promoter sequence implicate the site, including -107C, as a crucial element interacting with the activator that maintains hMLH1 gene expression.