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Exclusive KRAS mutation in microsatellite-unstable human colorectal carcinomas with sequence alterations in the DNA mismatch repair gene, MLH1.
- Source :
-
Gene [Gene] 2008 Nov 01; Vol. 423 (2), pp. 188-93. Date of Electronic Publication: 2008 Jul 22. - Publication Year :
- 2008
-
Abstract
- 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 MSI-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.
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Base Sequence
Codon
Female
Humans
Male
Middle Aged
MutL Protein Homolog 1
Proto-Oncogene Proteins p21(ras)
Adaptor Proteins, Signal Transducing genetics
Colorectal Neoplasms genetics
DNA Mismatch Repair
Microsatellite Instability
Mutation genetics
Nuclear Proteins genetics
Proto-Oncogene Proteins genetics
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0378-1119
- Volume :
- 423
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Gene
- Publication Type :
- Academic Journal
- Accession number :
- 18692554
- Full Text :
- https://doi.org/10.1016/j.gene.2008.07.014