The goals of this project center around the molecular genetic analysis of pathologic conditions of the human uterus, including endometrial carcinoma, endometriosis, and uterine leiomyoma (fibroids). Related studies include the molecular genetic analyses of human and rodent cancers associated with exposure in utero to diethylstilbestrol, human latent prostatic carcinomas, and hereditary breast and ovarian cancers with emphasis on the BRCA1 susceptibility locus. Significant progress has been made in defining the relevant oncogenes and tumor suppressor genes involved in the pathobiology of endometrial carcinoma. Several genes and chromosomal loci have been found to be predominantly involved in either type I, estrogen-related tumors, or type II, nonestrogen-related tumors. Notable among these are a gene on chromosome 2p responsible for a replication error phenotype (type I tumors), and a novel locus on chromosome 14q that is highly correlated with death from disease (type II tumors). Studies on endometriosis have identified a novel endometrial cDNA clone that is recognized by serum antibodies in women with endometriosis; the sequencing, characterization, and determination of clinical utility of this gene is in progress. Further studies were initiated that will attempt to correlate serum levels of organochlorine toxicants (e.g., dioxin, PCBs) with the presence or extent of endometriosis in human subjects. Efforts were begun to clone and characterize genes involved in uterine leiomyoma. The most frequent cytogenetic abnormality in these tumors is a balanced translocation involving chromosomes 12 and 14. A large number of candidate cDNAs have been cloned from the 12q15 region, and their characterization and possible involvement in myometrial tumorigenesis are under study. An analysis of human and rodent tumors induced by DES exposure has found an absence of mutations in the P53, RAS, and WT-1 genes. Future studies are designed to identify other, perhaps novel genomic loci relevant to DES carcinogenesis, as well as the molecular pathway of DES-induced genital tract developmental anomalies.
| 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 |
