The molecular genetics analysis of neoplastic conditions of the female genital tract including endometrial carcinoma, uterine sarcoma, uterine leiomyoma and ovarian carcinoma are under study. Significant progress has been achieved in defining the molecular genetic basis of these tumors including defects in pathways that normally function to maintain the stability of the genome. Analysis of these cancers, particularly endometrial cancer has defined a subset that has the molecular genetic phenotype of microsatellite instability. Microsatellite instability is the result of defective DNA mismatch repair, which normally functions to correct DNA replication errors. Inactivation of this pathway may involve mutation or epigenetic silencing of several genes. Current study involves the mechanism for the epigenetic inactivation as well as the contribution of this pathway to carcinogenesis. Specifically, we are addressing the question whether ovarian steroids play a role in silencing key genes involved in mismatch repair. Additionally, we have identified cell lines defective in the hPMS2 mismatch repair gene and complemented its function by cDNA transfection. The hPMS2 restored cells and also cells restored for hMLH1, hMSH2 and hMSH3/hMSH6 are being utilized in studies to determine whether there is an interaction between the cell cycle machinery and mismatch repair. The DNA repair process requires cellular arrest at certain stages of the cell cycle known as checkpoints. Current research is focused on understanding how the mismatch repair system coordinates with the cell cycle machinery to stop cell cycle progression and allow repair following exposure to damaging agents. Also under study are regions of allele loss on chromosomes 1, 10 and 14 in endometrial carcinomas and chromosome 7 in uterine leiomyoma. Mutational inactivation of the PTEN gene located on chromosome 10 was examined in endometrial neoplasm and found to be mutated in greater than 40% of cancers and about 20% of hyperplasias. These results indicate that PTEN is the most frequently altered gene in this cancer type suggesting a key functional role for this gene in the endometrium. Additional study of these chromosomal regions may lead to further identification of genes involved in endometrial or myometrial pathologies.
| Zhou, Y; Kato, H; Shan, D et al. (1999) Involvement of mutations in the DPC4 promoter in endometrial carcinoma development. Mol Carcinog 25:64-72 |
