"The""modification""Type Microsatellite Change in High Frequency Microsatellite Instability Colorectal Cancer Closely Relating to MLH1 and KRAS Mutation" / 现代生物医学进展

Microsatellite instability(MSI)was defined according to the frequency of positive findings in a panel of MSI markers.High frequency MSI(MSI-H)was the phenotype in which repeat sequences were extraordinarily unstable, and was considered to be the bona fide phenotype of DNA mismatch repair defection. However base substitutions in some well studied oncogenes or tumor suppressors were reported to be uncommon in MSI-H tumors. To explore this obvious contradiction, the relationship between MSI and KRAS gene mutations were studied in a panel of 76 human colorectal carcinomas, the whole exon of MLH1 and MSH2 were sequenced for MSI-H tumors. KRAS gene mutation was confirmed by similar frequencies in tumors of different MSI status. Intriguingly, all of the KRAS mutant MSI-H tumors harbored sequence alterations in MLH1gene, which was a key player in DNA mismatch repair system. This implied that in MSI-H tumors carrying MMR mutations, KRAS mutation were frequently and almost exclusively occurred. Furthermore, these MMR mutants were uniformly carrying a unique modification + jumping type MSI, which was different to MSI-H tumors without MLH1 or MSH2 gene mutations. This study shaded lights on the heterogeneity of MSI-H tumors, and implied the connection between modification type MSI and DNA mismatch defection.

The"modification"Type Microsatellite Change in High Frequency Microsatellite Instability Colorectal Cancer Closely Relating to MLH1 and KRAS Mutation / 现代生物医学进展

Microsatellite instability(MSI)was defined according to the frequency of positive findings in a panel of MSI markers.High frequency MSI(MSI-H)was the phenotype in which repeat sequences were extraordinarily unstable, and was considered to be the bona fide phenotype of DNA mismatch repair defection. However base substitutions in some well studied oncogenes or tumor suppressors were reported to be uncommon in MSI-H tumors. To explore this obvious contradiction, the relationship between MSI and KRAS gene mutations were studied in a panel of 76 human colorectal carcinomas, the whole exon of MLH1 and MSH2 were sequenced for MSI-H tumors. KRAS gene mutation was confirmed by similar frequencies in tumors of different MSI status. Intriguingly, all of the KRAS mutant MSI-H tumors harbored sequence alterations in MLH1gene, which was a key player in DNA mismatch repair system. This implied that in MSI-H tumors carrying MMR mutations, KRAS mutation were frequently and almost exclusively occurred. Furthermore, these MMR mutants were uniformly carrying a unique "modification" + "jumping" type MSI, which was different to MSI-H tumors without MLH1 or MSH2 gene mutations. This study shaded lights on the heterogeneity of MSI-H tumors, and implied the connection between "modification" type MSI and DNA mismatch defection.

The"modification"Type Microsatellite Change in High Frequency Microsatellite Instability Colorectal Cancer Closely Relating to MLH1 and KRAS Mutation / 现代生物医学进展

Microsatellite instability(MSI)was defined according to the frequency of positive findings in a panel of MSI markers.High frequency MSI(MSI-H)was the phenotype in which repeat sequences were extraordinarily unstable, and was considered to be the bona fide phenotype of DNA mismatch repair defection. However base substitutions in some well studied oncogenes or tumor suppressors were reported to be uncommon in MSI-H tumors. To explore this obvious contradiction, the relationship between MSI and KRAS gene mutations were studied in a panel of 76 human colorectal carcinomas, the whole exon of MLH1 and MSH2 were sequenced for MSI-H tumors. KRAS gene mutation was confirmed by similar frequencies in tumors of different MSI status. Intriguingly, all of the KRAS mutant MSI-H tumors harbored sequence alterations in MLH1gene, which was a key player in DNA mismatch repair system. This implied that in MSI-H tumors carrying MMR mutations, KRAS mutation were frequently and almost exclusively occurred. Furthermore, these MMR mutants were uniformly carrying a unique "modification" + "jumping" type MSI, which was different to MSI-H tumors without MLH1 or MSH2 gene mutations. This study shaded lights on the heterogeneity of MSI-H tumors, and implied the connection between "modification" type MSI and DNA mismatch defection.