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Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal
Johanna Kondelin1,2, Alexandra E Gylfe1,2, Sofie Lundgren1,2
1Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
Abstract:
Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8 Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. Cancer Res; 77(15); 4078-88. ©2017 AACR.
Insights
Microsatellite instability (MSI) in colorectal cancer causes mutations. Researchers identified new MSI target genes, AASDH and SLC9A8, by analyzing mutation rates and significance in patient tumors.
Area of Science:
- Genomics and Cancer Research
- Molecular Biology
- Bioinformatics
Background:
- Approximately 15% of colorectal cancers display microsatellite instability (MSI), a hallmark of mismatch repair deficiency.
- MSI leads to the accumulation of insertions and deletions (indels) in microsatellite regions, potentially affecting gene function and cellular growth.
- Identifying genes targeted by MSI is crucial for understanding colorectal cancer development and progression.
Purpose of the Study:
- To develop a statistical model to assess the significance of somatic background indel mutation rates in microsatellites.
- To systematically identify and catalog true MSI target genes in colorectal cancer.
- To pinpoint specific genes that are frequently mutated due to MSI and may drive tumor growth.
Main Methods:
- Development of a statistical model to evaluate indel mutation significance in microsatellites.
- Exome sequencing of 24 MSI colorectal cancer samples to identify indels in mononucleotide microsatellites.
- Analysis of 105 microsatellites from 71 genes in an additional 93 MSI colorectal cancer samples.
Main Results:
- A statistical model was established to assess the significance of somatic background indel mutation rates.
- Exome sequencing identified millions of indels across numerous microsatellites in MSI colorectal cancers.
- The genes aminoadipate-semialdehyde dehydrogenase (AASDH) and solute transporter SLC9A8 were identified as high-confidence MSI target genes based on mutation significance and clonality.
Conclusions:
- The study provides a systematic profiling of somatic background mutation rates in protein-coding mononucleotide microsatellites.
- AASDH and SLC9A8 are identified as key MSI target genes in colorectal cancer.
- This work enables a comprehensive cataloging of MSI targets, advancing our understanding of MSI-driven tumorigenesis.
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