期刊
GENE
卷 423, 期 2, 页码 188-193出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.gene.2008.07.014
关键词
Microsatellite instability (MSI); Replication errors; DNA mismatch repair; Mutator phenotype; Base substitutions
资金
- Ministry of Health, Labor and Welfare
- Ministry of Education, Science, Sports and Culture of Japan
- Honjo International Scholarship Foundation
Microsatellite instability (MSI) is regarded as reflecting defective DNA mismatch repair (MMR). MMR defects lead to an increase in point mutations, as well as repeat instability, on the genome. However, despite the highly unstable microsatellites, base substitutions in representative oncogenes or tumor suppressors are extremely infrequent in MSI-positive tumors. Recently. the heterogeneity in MSI-positive colorectal tumors is pointed out, and the 'hereditary' and 'sporadic settings' are proposed. Particularly in the former, base substitution mutations in KRAS are regarded as relatively frequent. We sequenced the KRAS gene in a panel of 76 human colorectal carcinomas in which the MSI status has been determined. KRAS mutations were detected in 22 tumors (28.9%). Intriguingly, all of the KRAS-mutant MISI-H (high) tumors harbored sequence alterations in an essential MMR gene, MLH1, which implies that KRAS mutation more frequently and almost exclusively occurs in MMR gene-mutant MSI-H tumors. Furthermore, in contrast with the prevailing viewpoint, some of these tumors are derived from sporadic colorectal cancer patients. The tight connection between MMR gene mutation and KRAS mutation may suggest previously unrecognized complexities in the relationship between MSI and the mutator phenotype derived from defective MMR. (c) 2008 Elsevier B.V. All rights reserved.
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