Molecular Pathology Of Ec

Numerous recent studies have been published on the molecular pathology of EC (10-12,24). The molecular hallmark of sporadic type I carcinomas is inactivation of the PTEN tumor suppressor gene. Loss of PTEN function is the most common genetic defect in ECs, especially in the type I variety (10,25). It appears that this nonphysiological loss of PTEN may occur in the earliest stages of endometrial carcinogenesis, which can be seen in the persistent estrus of anovulatory women (10,25), thus, suggesting the emergence of a monoclonal population of neoplastic cells (www.endometrium.org) (26). Studies of PTEN in normal endometrium show strong expressions in estrogen-dominated proliferative phase and weaker expression in progesterone-added secretory phase. Thus, it is possible that PTEN-deficient tumor cells might have a survival advantage in an estrogen-rich environment (10,24). Besides PTEN, other molecular markers include the protooncogenes bcl-2, and bax, which are overexpressed in these tumors. Features helpful in differentiating high-grade type I tumors from type II tumors are, strong nuclear p-catenin immunostaining in the type I cancers and strong e-cadherin immunostaining in the type II cancers (27). As expected, cell proliferation markers, such as MIB-1 and Ki-67 are usually lower in type I EC compared with the type II EC (Table 2).

Thus, three distinct molecular pathways are seen in the pathogenesis of EC. First, PTEN loss in sporadic occurrences of the usual, type I low-grade endometrioid cancers. Second, p53 mutation in sporadic cases of the rarer, type II high-grade serous cancers. Third, microsatellite instability (MSI), as a result of mutations in several MMR genes in the hereditary ECs associated with colorectal carcinoma CRCs in the Lynch syndrome. Table 3 shows a comparison of sporadic and HNPCC-associated ECs.

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