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Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype
H Yamamoto1, H Sawai, M Perucho
1The Burnham Institute, La Jolla Cancer Research Center, California 92037, USA.
Abstract:
An exacerbated genomic instability characterizes hereditary and sporadic gastrointestinal cancer of the microsatellite mutator phenotype (MMP), generating somatic frameshift mutations in genes containing mononucleotide repeats. We have recently shown that approximately 50, 40, and 30% of MMP+ colon tumors harbor frameshift mutations in (G)8, (A)8, and (C)8 tracks within the proapoptotic gene BAX and the hMSH3 and hMSH6 DNA mismatch repair genes, respectively. Here we report a higher incidence of frameshift mutations in these 3 genes in a panel of 25 MMP+ gastric adenocarcinomas: 64% in BAX and hMSH3, and 52% in hMSH6. These results support a multiple mutator gene model for the stepwise unfolding of the MMP and further illustrate the importance of the escape from apoptosis in gastrointestinal cancer. The tumor suppressor role played by BAX is also supported by the finding of other somatic BAX mutations, including recurrent missense mutations, not only in gastrointestinal cancer of the MMP but also in gastrointestinal cancer without the MMP.
Insights
Microsatellite mutator phenotype (MMP) gastrointestinal cancers show increased mutations in BAX, hMSH3, and hMSH6 genes. Gastric tumors exhibit higher mutation rates than colon tumors, highlighting apoptosis escape in cancer development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Genomic instability, particularly the microsatellite mutator phenotype (MMP), is a hallmark of gastrointestinal cancers.
- Somatic frameshift mutations in mononucleotide repeats are common in MMP-positive (MMP+) cancers.
- Previous studies identified mutations in BAX, hMSH3, and hMSH6 in MMP+ colon tumors.
Purpose of the Study:
- To investigate the incidence of frameshift mutations in BAX, hMSH3, and hMSH6 in MMP+ gastric adenocarcinomas.
- To compare mutation frequencies in these genes between gastric and colon MMP+ tumors.
- To further elucidate the role of apoptosis escape and the multiple mutator gene model in gastrointestinal cancer.
Main Methods:
- Analysis of frameshift mutations in BAX, hMSH3, and hMSH6 genes within a panel of 25 MMP+ gastric adenocarcinomas.
- Comparison of mutation data with previously reported findings in MMP+ colon tumors.
Main Results:
- A higher incidence of frameshift mutations was observed in MMP+ gastric adenocarcinomas compared to MMP+ colon tumors.
- Specifically, 64% of gastric tumors had mutations in BAX and hMSH3, and 52% had mutations in hMSH6.
- The study also identified other somatic BAX mutations, including missense mutations, in gastrointestinal cancers both with and without the MMP.
Conclusions:
- The findings support a multiple mutator gene model for the progression of the MMP in gastrointestinal cancers.
- The results underscore the significance of escaping apoptosis in the development of gastrointestinal cancer.
- The tumor suppressor role of BAX is further supported by the identification of diverse somatic mutations in various gastrointestinal cancer contexts.