Exclusive KRAS mutation in microsatellite-unstable human colorectal carcinomas with sequence alterations in the DNA mismatch repair gene, MLH1

Yan Zhao, Kaname Miyashita, Takayuki Ando, Yoshihiro Kakeji, Takeharu Yamanaka, Kenichi Taguchi, Toshikazu Ushijima, Shinya Oda, Yoshihiko Maehara

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)188-193
Number of pages6
JournalGene
Volume423
Issue number2
DOIs
Publication statusPublished - Nov 1 2008

All Science Journal Classification (ASJC) codes

  • Genetics

Fingerprint Dive into the research topics of 'Exclusive KRAS mutation in microsatellite-unstable human colorectal carcinomas with sequence alterations in the DNA mismatch repair gene, MLH1'. Together they form a unique fingerprint.

  • Cite this

    Zhao, Y., Miyashita, K., Ando, T., Kakeji, Y., Yamanaka, T., Taguchi, K., Ushijima, T., Oda, S., & Maehara, Y. (2008). Exclusive KRAS mutation in microsatellite-unstable human colorectal carcinomas with sequence alterations in the DNA mismatch repair gene, MLH1. Gene, 423(2), 188-193. https://doi.org/10.1016/j.gene.2008.07.014