Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes

Item Type:	Article
Title:	Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes
Creators Name:	Woerner, S.M. and Benner, A. and Sutter, C. and Schiller, M. and Yuan, Y.P. and Keller, G. and Bork, P. and Doeberitz, M.V. and Gebert, J.F.
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 TGFβRII 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.
Keywords:	ByStander Genes, Coding Microsatellite, Microsatellite Instability, Mismatch Repair, Real Common Target Genes
Source:	Oncogene
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Volume:	22
Number:	15
Page Range:	2226-2235
Date:	17 April 2003
Official Publication:	https://doi.org/10.1038/sj.onc.1206421
PubMed:	View item in PubMed

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