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Frameshift mutations of Wnt pathway genes AXIN2 and TCF7L2 in gastric carcinomas with high microsatellite instability
Min Sung Kim1, Sung Soo Kim, Chang Hyeok Ahn
1Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Abstract:
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.
Insights
Frameshift mutations in AXIN2 and TCF7L2 genes are common in gastric cancers with high microsatellite instability (MSI). These mutations may contribute to gastric cancer development by disrupting Wnt signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Microsatellite instability (MSI) is a hallmark of certain cancers, including gastric carcinoma.
- The Wnt signaling pathway plays a crucial role in cancer development, and its deregulation is frequently observed in malignancies.
- Genes like AXIN2 and TCF7L2, containing mononucleotide repeats, are implicated in Wnt pathway regulation and are potential tumor suppressors.
Purpose of the Study:
- To investigate the presence and frequency of frameshift mutations in the AXIN2 and TCF7L2 genes within gastric carcinomas exhibiting different MSI statuses.
- To determine if these mutations are associated with the development of gastric cancers characterized by high MSI.
Main Methods:
- Analysis of AXIN2 exon 8 and TCF7L2 exon 14 in gastric carcinoma samples.
- Categorization of samples based on MSI status: high MSI (MSH-H), low MSI (MSL), and without MSI (MSS).
- Single-strand conformation polymorphism (SSCP) analysis was employed to detect frameshift mutations.
Main Results:
- Frameshift mutations in AXIN2 and TCF7L2 were exclusively detected in gastric carcinomas with high MSI.
- AXIN2 mutations were found in 28.1% and TCF7L2 mutations in 18.8% of high MSI gastric cancers.
- Approximately 40.6% of high MSI gastric carcinomas harbored at least one mutation in either AXIN2 or TCF7L2.
Conclusions:
- Frameshift mutations in AXIN2 and TCF7L2 are prevalent in gastric carcinomas with high MSI.
- These mutations likely contribute to gastric cancer pathogenesis by altering Wnt signaling in MSI-high tumors.
- Targeting Wnt signaling could be a potential therapeutic strategy for gastric cancers with these specific mutations.
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