Mutations of the human MUT S homologue 6 gene in ampullary carcinoma and gastric cancer.

Abstract

MSH6 has been implicated in repair of single base mispairs and single-base deletion/insertion mutations. Established MSH6-null mice present a frequent occurrence of gastrointestinal tumors without microsatellite instability (MI), suggesting the possibility of the APC gene being a mutational target. Because human ampullary carcinomas and gastric cancers manifest frequent missense or I-base deletion mutations in cancer-related genes such as p53 and TGFbeta-RII, we suspected that the hMSH6 gene mutation might play a role in the carcinogenesis process. Out of the whole coding sequences, hMSH6 (C)8 (codons 1085-1087) and hMSH3 (A)8 repeats (codons 381-383) have been shown to be hotspots for frameshift mutations in a certain group of cancers, contributing to an increased genomic instability. We therefore investigated mutations of hMSH6 (C)8 and hMSH3 (A)8 in association with microsatellite mutator phenotype (MMP) in 18 ampullary carcinomas and 30 gastric cancers. In addition, overexpression of the P53 protein and mutational status of APC (AG)5 (codons 1462-1465) and (A)6 (codons 1554-1556) repeats were also investigated as a potential target of genetic instability secondary to MSH6 dysfunction. Mutation of the hMSH6 gene was not found in ampullary carcinomas and was irrelevant to TGFbeta-RII gene mutation. Mutation of the hMSH6 gene was observed in a subset of gastric cancers (4/30, 13.3%), but was not associated with P53 overexpression or APC gene mutation. In contrast to MSH6-null mice that do not show MI, hMSH6 gene mutation in human gastric cancers was closely correlated with MMP (3/10 MMP vs. 1/20 non-MMP). In conclusion, hMSH6 mutation appears only in association with MMP and may underlie augmented MI, resulting in missense or I-base frameshift mutations in other genes in human gastric cancers.