Frameshift mutations of Wnt pathway genes AXIN2 and TCF7L2 in gastric carcinomas with high microsatellite instability.

Frameshift mutations of genes with mononucleotide repeats are features of colorectal and gastric cancers with microsatellite instability (MSI). Deregulation of Wnt pathway is involved in the mechanisms of cancer development, and mutations of the Wnt-pathway genes have frequently been detected in cancers, indicating somatic mutations are important deregulation mechanisms of the Wnt signaling in cancer development. Both AXIN2 and TCF7L2 genes in the Wnt pathway possess mononucleotide repeats in their coding sequences and are considered as candidate tumor suppressor genes. The aim of this study was to see whether AXIN2 and TCF7L2 are altered by frameshift mutations in gastric carcinomas with MSI. For this, we analyzed human AXIN2 exon 8 and TCF7L2 exon 14 in 32 gastric carcinomas with high MSI, 13 gastric carcinomas with low MSI, and 47 gastric carcinomas without MSI by a single-strand conformation polymorphism analysis. Overall, we detected 9 AXIN2 and 6 TCF7L2 frameshift mutations in the mononucleotide repeats in the cancers with MSH-H, and all of them were found in MSH-H cancers (AXIN2, 28.1%; TCF7L2, 18.8%). Of the 32 high MSI cancers, 13 cancers (40.6%) harbored at least one of AXIN2 and TCF7L2 mutation, whereas 19 cancers (59.4%) harbored neither. The present data indicate that frameshift mutations in both AXIN2 and TCF7L2 genes are common in gastric carcinomas with high MSI and suggest that these mutations may contribute to development of gastric cancers with high MSI by deregulating the Wnt signaling in the affected cancer cells.