Molecular alterations associated with cyclin D1 overexpression in endometrial cancer

Cyclin DI is frequently overexpressed in human neoplasias by gene rearrangement and amplification. In addition, Ras, PTEN and beta-catenin appear to modulate cyclin DI levels. Since the causes of cyclin DI overexpression are poorly understood in EC, we investigated whether or not this alteration is due to cyclin DI gene amplification or to RAS, PTEN and beta-catenin mutation. We analyzed cyclin DI expression in 18 AEHs, 65 EECs and 27 NEECs by immunohistochemistry as well as CCNDI gene amplification by FISH. In EECs, mutations in K-RAS, PTEN, beta-catenin and CCNDI were studied by PCR-SSCP and sequencing and MSI was evaluated by analyzing BAT-25 and BAT-26 microsatellites. Contingency tests were used to evaluate the relationships between variables. Cyclin DI overexpression was not observed in AEHs but was present in 13.8% of EECs and 11.2% of NEECs (p = 0.031). CCNDI amplification was more frequent in NEECs (26.3%) than in EECs (2.1%) (p = 0.002). In EECs, cyclin DI overexpression was not associated with mutations in K-RAS, PTEN or beta-catenin. However, in EECs with beta-catenin mutations, cyclin DI was expressed mainly by cells expressing beta-catenin in the cytoplasm and nucleus but not in those with membranous expression. Finally, cyclin DI overexpression was associated with MSI (p = 0.047). The molecular alterations associated with cyclin DI overexpression differ in the 2 clinicopathologic types of EC. Cyclin DI overexpression is associated with gene amplification in NEECs and with nucleocytoplasmic expression of beta-catenin and MSI in EECs. (C) 2004 Wiley-Liss, Inc.