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

✍ Scribed by Yasuo Imai; Tohru Inoue; Takatoshi Ishikawa

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: French
• Weight: 98 KB
• Volume: 78
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19981123)78:5<576::aid-ijc8>3.0.co;2-5

✦ Synopsis

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 1-base deletion mutations in cancer-related genes such as p53 and TGF␤-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 TGF␤-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 1-base frameshift mutations in other genes in human gastric cancers.