The molecular genetics analysis of neoplastic conditions of the female genital tract including emdometrial 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. Analysis of these cancers, particularly endometrial cancer has defined a subset that have the molecular genetic phenotype of microsatellite instability. Microsatellite instability in individuals with hereditary non-polyposis colorectal carcinoma, is the result of inherited alterations in genes involved in DNA mismatch repair. Mutational analysis fails to find alterations of the HNPCC genes in many sporadic endometrial andovarian carcinomas with microsatellite instability. Several candidate genes (based on sequence similarity to other mismatch repair genes) were analyzed for alterations in these samples. Of these, hMSH3, was found to be altered in several endometrial tumors and cell lines. Introduction of a normal copy of hMSH3 into a hMSH3 mutant cell line restored certain aspects of defective DNA repair and drastically reduced the micro-satellite instability in this cell line. These results indicate that additional genes function to maintain the fidelity of replication and that hMSH3 plays a key role in this process. In addition studies are underway to determine whether there is an interaction between the cell cycle machinery and mismatch repair. The DNA repair process requires a 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES023001-07
Application #
2574317
Study Section
Special Emphasis Panel (LMC)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1996
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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