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Published on: June 26, 2020
Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes
Stefan M Woerner1, Axel Benner, Christian Sutter
1Department of Molecular Pathology, Institute of Patholofy, University of Heidelberg, Heidelberg, Germany.
Abstract:
DNA mismatch repair deficiency is observed in about 15% of human colorectal, gastric, and endometrial tumors and in lower frequencies in a minority of other tumors thereby causing insertion/deletion mutations at short repetitive sequences, recognized as microsatellite instability (MSI). Evolution of tumors, including those with MSI, is a continuous process of mutation and selection favoring neoplastic growth. Mutations in microsatellite-bearing genes that promote tumor cell growth in general (Real Common Target genes) are assumed to be the driving force during MSI carcinogenesis. Thus, microsatellite mutations in these genes should occur more frequently than mutations in microsatellite genes without contribution to malignancy (ByStander genes). So far, only a few Real Common Target genes have been identified by functional studies. Thus, comprehensive analysis of microsatellite mutations will provide important clues to the understanding of MSI-driven carcinogenesis. Here, we evaluated published mutation frequencies on 194 repeat tracts in 137 genes in MSI-H colorectal, endometrial, and gastric carcinomas and propose a statistical model that aims to identify Real Common Target genes. According to our model nine genes including BAX and TGFbetaRII were identified as Real Common Targets in colorectal cancer, one gene in gastric cancer, and three genes in endometrial cancer. Microsatellite mutations in five additional genes seem to be counterselected in gastrointestinal tumors. Overall, the general applicability, the capacity to unlimited data analysis, the inclusion of mutation data generated by different groups on different sets of tumors make this model a useful tool for predicting Real Common Target genes with specificity for MSI-H tumors of different organs, guiding subsequent functional studies to the most likely targets among numerous microsatellite harboring genes.
Insights
DNA mismatch repair deficiency causes microsatellite instability (MSI) and tumor growth. This study identifies key cancer-driving genes (Real Common Target genes) in MSI-H colorectal, gastric, and endometrial cancers using a novel statistical model.
Area of Science:
- Oncology
- Genetics
- Bioinformatics
Background:
- DNA mismatch repair deficiency (dMMR) is linked to microsatellite instability (MSI) in ~15% of colorectal, gastric, and endometrial tumors.
- Tumorigenesis involves mutation and selection, with MSI-driven carcinogenesis potentially driven by mutations in specific genes (Real Common Target genes).
- Identifying these target genes is crucial for understanding MSI-driven cancer, but few have been functionally validated.
Purpose of the Study:
- To develop and apply a statistical model to identify Real Common Target genes in MSI-H cancers.
- To analyze microsatellite mutation frequencies across 137 genes in MSI-H colorectal, endometrial, and gastric carcinomas.
- To distinguish between genes driving malignancy and those unaffected by MSI in cancer development.
Main Methods:
- Evaluation of published mutation frequencies for 194 repeat tracts in 137 genes from MSI-H colorectal, endometrial, and gastric carcinomas.
- Development of a statistical model to differentiate Real Common Target genes from ByStander genes based on mutation frequency.
- Analysis of mutation data from diverse studies and tumor types to ensure model generalizability.
Main Results:
- The statistical model identified nine Real Common Target genes in colorectal cancer (e.g., BAX, TGFbetaRII), one in gastric cancer, and three in endometrial cancer.
- Microsatellite mutations in five genes appeared to be counterselected in gastrointestinal tumors.
- The model demonstrated applicability across different tumor types and datasets, highlighting its utility in predicting MSI-specific targets.
Conclusions:
- The developed statistical model effectively identifies Real Common Target genes in MSI-H tumors.
- This approach aids in understanding MSI-driven carcinogenesis and guides functional studies toward key genes involved in tumor growth.
- The findings provide valuable insights into the genetic landscape of MSI-H cancers across different organs.
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