Identification of Target Genes in the Endometrial Carcinomas with Microsatellite Mutator Phenotype / 대한산부인과학회지

OBJECTIVE: Recent molecular genetic studies have revealed that two major types of genomic instabilities, chromosomal instability and microsatellite instability (MSI), exist in the endometrial carcinomas. Tumors with microsatellite mutator phenotype (MMP) are caused by defects in DNA mismatch repair genes. MMP tumors are believed to progress by accumulating frameshift mutations in coding microsatellite sequences of various cancer related genes including tumor suppressor genes, apoptosis related genes and DNA repair genes. Thus, the identification of the specific target genes in the MMP endometrial carcinomas is important for the elucidation of molecular pathogenesis of endometrial carcinomas. METHODS: We classified the MMP endometrial carcinomas and evaluated the frameshift mutations of the 11 genes containing coding microsatellite sequences by using 34 endometrial carcinomas and 4 MMP endometrial carcinoma cell lines. RESULTS: MSI was found in 6 of 34 endometrial carcinomas. In the endometrial carcinoma tissues, frequent mutations were found in TAF1B (68%), HT001 (50%), SLC23A1 (50%) and ACVR II (50%) in the MMP endometrial carcinoma tissues. The other 7 genes were infrequently mutated. Mutations of these target genes were more frequent in MMP endometrial carcinoma cell lines. CONCLUSION: we identified specific target genes in MMP endometrial carcinomas. These data demonstrate the mechanism of tumor progression in the MMP endometrial carcinomas.

Expression Pattern of DNA Mismatch Repair Genes in Tumors of Microsatellite Mutator Phenotype

Microsatellite mutator phenotype (MMP) tumors were reported in a subset of gastrointestinal carcinomas. The molecular pathogenesis of MMP tumors shows defects in the DNA mismatch repair genes, and also many germline and somatic mutations were reported in the MMP tumors. However, the detection of genetic defects in the MMP tumors is very difficult, mainly because many genes are included in the DNA mismatch repair genes. This study was undertaken to determine the best strategy for detecting defects in the DNA mismatch repair genes in gastrointestinal carcinomas. One of the effective ways for detecting defects in DNA mismatch repair genes is to screen the MMP tumors and evaluate the products of DNA mismatch repair genes by performing the multiplex RT-PCR method. We have screened the MMP tumors by using 5 microsatellite markers in the 12 cancer cell lines, 120 colon carcinomas and 99 gastric carcinomas and found 6 MMP cell lines, 10 MMP colon cancers, and 9 MMP gastric carcinomas. In addition, we evaluated 6 DNA mismatch repair gene products (hMSH2, hMSH3, hMSH6, hMLH1, hPMS1 and hPMS2) by multiplex RT-PCR analysis and found decreased expression of the DNA mismatch repair genes in 5 (hMSH6 in DLD-1 and HCT-15; hMSH2 in LoVo; hMLH1 and hMSH3 in HCT-116; hMLH1 in SNU-638) out of 6 MMP cell lines. We also found a decreased expression of hMLH1 in 3 out of 10 MMP colon carcinomas, and in 6 out of 9 MMP gastric carcinomas. Our results indicate that the expression analysis of the DNA mismatch repair genes by multiplex RT-PCR method can reduce the number of genes subjected to mutational analysis and is convenient for screening the responsible DNA mismatch repair genes.