Molecular Genetic Profiles of Serous and Endometrioid Endometrial Cancers, Genes Downregulated in Endometrial Cancers, and the Role of Epigenetics

摘要

Endometrial cancers, like most other malignancies, develop, in part, as the result of oncogene activation and tumor suppressor and DNA repair gene inactiva-tions. Available molecular data suggest that endometrial cancers of endometrioid and nonendometrioid histology develop by distinct etiologies. Endometrioid lesions are typified by PTEN, CTNNBl, and KRAS2 mutations, DNA mismatch repair deficiency, as evidenced by microsatellite instability, and are usually near diploid. Nonendometrioid histologies are characterized by mutation of TP53, overexpression of Her-2/neu, and are usually nondiploid, suggesting widespread chromosomal instability. Although these changes are observed in many endometrial cancers, they do not occur universally, suggesting that there are unrecognized pathways involved in the development of endometrial cancer. We examined the prevalence of these prototypical defects in a panel of 87 cancers. Interestingly, more than half the cancers did not contain mutations of PTEN, KRAS2, and TP53, or have microsatellite instability. Based, in part, on this observation, we believe that epigenetic mechanisms likely play a major role in the development of some endometrial cancers. Multiple epigenetic mechanisms are likely involved, including loss of imprinting, chromatin remodeling, and promoter hypermethylation. Our group has recently evaluated the role of promoter methylation in endometrial carcinogenesis and has found that methylation of specific promoters varies between endometrioid and nonendometrioid histologic types. We have also performed in vitro manipulation of endometrial carcinoma cells with agents that demethylate promoters prior to microarray analysis to identify genes that are up-or downregulated. In addition, we have analyzed a panel of endometrial cancers using expression microarrays to identify downregulated genes in both endometrioid and nonendometrioid endometrial cancers. Following a cross-referencing of both array databases, genes common to both the global expression of primary endometrial cancers and in vitro experiments can be identified.