Lynch syndrome is an autosomal dominant colorectal cancer susceptibility syndrome caused by a dysfunction of DNA mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2. However, the interpretation of certain changes in the mismatch repair genes is perplexing, as these changes do not necessarily affect the function of the protein. The pathogenicity of the hMLH1 1151T↷A variant, which results in an amino-acid substitution of valine for aspartic acid at codon 384 (V384D), is also controversial. This study was undertaken to assess the clinicopathological features of colorectal cancer patients harboring the hMLH1 V384D variant. Two independent Japanese cohorts, comprising 670 colorectal cancer patients and 332 cancer-free controls, respectively, were genotyped by polymerase chain reaction (PCR)-RFLP. The allele frequency of V384D was 0.75% in the control group and 3.1% in the colorectal cancer group (p<0.001). Thus, the V384D variant was associated with increased colorectal cancer susceptibility. However, only 5% of the colorectal cancer patients carrying the V384D variant had high micro-satellite instability; most had microsatellite-stable cancer. Additionally, these patients had no clear familial history of Lynch syndrome-related tumors. The combined results indicate that hMLH1 V384D allele frequency was 4.1-fold higher in the colorectal cancer group than in the control group. Thus, the hMLH1 V384D variant may contribute to the development of microsatellite-instable as well as -stable colorectal cancer.

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