Molecular markers in endometrial hyperplasia

Endometrial hyperplasias show most of the molecular changes observed in endometrial carcinomas. PTH-rp, a growth factor, and LIF, a cytokine are over-expressed in endometrial hyperplasias, particularly in the complex atypical hyperplasia group. However, other growth factors and cytokines such as IGF-1, EGF, TNF-? and IL-1? are decreased in both types of hyperplasia. Similar to growth factors, growth factor receptors such as estrogen receptor and androgen receptor also increase in hyperplastic endometrium except in atypical hyperplasia group. The mutant form of RAS, KRAS, which is a signal transducer protein, acts in the pre-malignant phase of endometrial neoplasia. Another member of the RAS signaling pathway, BRAF, may also be altered in endometrial hyperplasias. Among the cell cycle regulators, basic abnormalities are observed in cyclin D1 and cyclin A. Both cyclins increase gradually from proliferative endometrium to endometrial hyperplasia and carcinoma. Rb2/p130 and cables are the two cycle-associated proteins, acting as a negative regulator that are down-regulated in the hyperplasia-carcinoma sequence. Molecular alteration of the ?-catenin gene in atypical hyperplasia and cancer, but not in simple or complex hyperplasia without atypia, suggests that it plays an important role in endometrial carcinogenesis. Derangements in the tumor suppressor gene, PTEN, are the most frequent genetic alteration observed in endometrial hyperplasias. PTEN inactivation seems to occur as an initiating event in endometrial carcinogenesis since it takes place in both atypical hyperplasia and carcinoma. Over-expression of BCL-2, an anti-apoptotic marker, is also associated with the generation of endometrial hyperplasia without atypia and it may be associated with the progression from endometrial hyperplasia to endometrial carcinoma. A significant number of endometrial hyperplasias harbor mutations in DNA mismatch repair genes, particularly methylation of the promoter region of hMLH1 gene. Hypermethylation of hMLH1 has been presumed to be an early event in the carcinogenesis of endometrial carcinoma. hTERT, Cathepsin D, MMPs and TIMPs have been studied less frequently but they also undergo significant alterations in endometrial hyperplasias. Overall, microsatellite instability and mutations of PTEN, KRAS and ?-catenin genes are the most common molecular alterations observed in endometrial hyperplasias. All these molecular markers are not only potential tumor markers for clinical use but also provide further evidence linking atypical hyperplasia and endometrial carcinoma, thus contributing to our understanding of endometrial carcinogenesis