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Low mutation incidence in polymorphic noncoding short mononucleotide repeats in gastrointestinal cancer of the
Koichi Suzuki1, Tomoko Dai, Ikuko Suzuki
1The Burnham Institute, La Jolla Cancer Center, La Jolla, California 92037, USA.
Abstract:
Frameshifts in short mononucleotide tracts (SMT) in genes, such as TGFbetaRII and BAX, are common in gastrointestinal tumors of the microsatellite mutator phenotype (MMP). The significance of less common mutations has been recently challenged because frequencies as high as 50% were reported in some noncoding SMTs in MMP colon cancer cell lines (L. Zhang, et al., Cancer Res., 61: 3801-3805, 2001). We did not confirm these findings after examining >50 MMP gastrointestinal cancers for mutations in eight SMT loci with the highest reported frequencies. In three of these loci, no clonal mutations were detected, and they were infrequent (2.9-6.7%) in the other five. Length polymorphisms are frequent (25.7-43.9%) in one-half of these SMTs, suggesting an explanation for the discrepancy. Because of the peculiar features of MMP tumors, low prevalence of mutations in cancer genes may not be a disqualifying criterion for their functionality.
Insights
Frameshift mutations in short mononucleotide tracts (SMT) are common in microsatellite mutator phenotype (MMP) gastrointestinal cancers. However, this study found low mutation frequencies in key SMT loci, suggesting length polymorphisms may explain previous high-incidence reports.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Frameshift mutations in short mononucleotide tracts (SMT) are frequently observed in genes like TGFbetaRII and BAX within gastrointestinal tumors exhibiting the microsatellite mutator phenotype (MMP).
- Recent studies suggested high frequencies (up to 50%) of mutations in noncoding SMTs in MMP colon cancer cell lines, challenging the significance of less common mutations.
Purpose of the Study:
- To investigate and validate the reported high frequencies of mutations in SMT loci within gastrointestinal cancers of the microsatellite mutator phenotype (MMP).
- To determine the actual prevalence of mutations in specific SMT loci and explore potential reasons for discrepancies with previous findings.
Main Methods:
- Analysis of >50 gastrointestinal cancers from patients with the microsatellite mutator phenotype (MMP).
- Examination of mutations in eight SMT loci with previously reported high frequencies.
- Assessment of mutation prevalence and detection of length polymorphisms in the selected SMT loci.
Main Results:
- Three of the eight examined SMT loci showed no detectable clonal mutations in MMP gastrointestinal cancers.
- The remaining five SMT loci exhibited infrequent mutations, with frequencies ranging from 2.9% to 6.7%.
- High frequencies of length polymorphisms (25.7-43.9%) were observed in half of the investigated SMTs, potentially explaining prior discrepancies.
Conclusions:
- The findings do not support the previously reported high mutation frequencies in key SMT loci in MMP gastrointestinal cancers.
- Length polymorphisms in SMTs may be a significant factor contributing to discrepancies in mutation frequency data.
- The functional significance of mutations in cancer genes within MMP tumors should be evaluated considering these findings, as low prevalence may not exclude functionality.