Evolution of instability at coding and non-coding repeat sequences in human MSI-H colorectal cancers
| Autor: | Alex Duval, Barry Iacopetta, Emmanuel Tubacher, Sandra Rolland, Richard Hamelin, Gilles Thomas, Aurore Compoint |
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| Rok vydání: | 2001 |
| Předmět: |
Candidate gene
DNA Repair Base Pair Mismatch Biology medicine.disease_cause Polymerase Chain Reaction Evolution Molecular Biomarkers Tumor Tumor Cells Cultured Genetics medicine Humans Molecular Biology Gene Genetics (clinical) Repetitive Sequences Nucleic Acid Mutation General Medicine Phenotype Rad50 Disease Progression DNA mismatch repair Human genome Colorectal Neoplasms Carcinogenesis |
| Zdroj: | Human Molecular Genetics. 10:513-518 |
| ISSN: | 1460-2083 |
| DOI: | 10.1093/hmg/10.5.513 |
| Popis: | A number of human genes containing coding mononucleotide repeat sequences are particularly prone to mutations in tumors with defects in mismatch repair (MMR) genes (MSI-H cancers). In a large series of MSI-H colorectal tumors, we looked for mutations in 25 coding repeats contained in eight genes already known to be mutated in these cancers or in 17 other genes with an expected role in carcinogenesis. Mutations were found in 19 of the 25 candidate genes. Using a maximum likelihood statistical method, they were separated into two different groups that differed significantly in their mutation frequencies, and were likely to represent mutations that do or do not provide selective pressures during MSI-H tumoral progression, respectively. Three new target genes were found (GRB-14, RHAMM, RAD50). Our results provide evidence that MSI-H tumoral progression involves the cumulative mutations of a large number of genes. For each MSI-H tumor we calculated indexes representing the number of mutations found in genes of these groups. We also evaluated a shortening index at both the Bat-25 and Bat-26 non-coding mononucleotide tracts that are known to be almost always unstable in MSI-H cancers. A significant correlation was observed between instability at both coding and non-coding repeats, suggesting that Bat-25 and Bat-26 could be used as simple phenotypical markers of the tumoral evolution. A preferential order of mutations was deduced. During this process, hMSH3 alterations, a target gene encoding for a MMR protein, was found to play an important role by increasing the instability phenomenon characterizing these cancers. |
| Databáze: | OpenAIRE |
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