5, 6 Also, passenger mutations occur under MSI and therefore statistical models have been applied to distinguish real driver genes from genes with passenger mutations. 4 Well-established MSI CRC target genes include TGFBR2 and BAX. 3 Using a candidate gene strategy, a number of genes have been proposed as MSI target genes based on a high mutation frequency in coding mononuclotide tracts. Mutations that promote tumourigenesis are selected for and are frequently observed in MSI tumors. MSI-associated insertion and deletion mutations in the coding regions of the genome lead to frameshifts, resulting in truncation or other alteration of the protein product. Large numbers of random mutations occur throughout the genome in the cells with a defective MMR machinery. 2 This type of genetic instability is a key feature of tumorigenesis in hereditary nonpolyposis colorectal cancer (HNPCC) and a subset of sporadic colorectal cancers (CRCs) and carcinomas of the stomach and endometrium. 1In sporadic CRC, MSI is typically caused by epigenetic silencing of the MLH1 promoter through aberrant methylation. MSI occurs as a consequence of a germline defect and a subsequent somatic inactivation of the wild-type allele of one of the key genes involved in this system, MLH1, MSH2, MSH6, and PMS2. Defects in the MMR system lead to genetic instability referred to as microsatellite instability (MSI). This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development.ĭNA mismatch repair (MMR) system recognizes and removes misincorporations and slippage errors occurring in normal DNA replication. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 6–10 bp). All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6–10 bp in length. Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in ∼ 15% of all colorectal cancers (CRCs).
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