High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus

Telomerase activity, a mechanism granting cellular immortality, has been de tected in most cancer entities, but its association with clinical, histopat hologic, and prognostic parameters is not fully understood. We investigated whether quantitative telomerase levels are correlated to established progn ostic factors, telomere lengths, cell cycle kinetics, and the clinical cour se in endometrioid adenocarcinoma of the uterus (EC). A modified telomeric repeat amplification protocol (TRAP) was used to quantify the relative telo merase activity in a series of 53 primary tumors. Mean telomere length was determined by Southern blot analysis. Cell cycle kinetics were studied immu nohistochemically on paraffin sections using monoclonal antibodies to 2 dis tinct proliferation-specific proteins: Ki-67, which is expressed throughout the cell cycle, and a novel cell cycle-associated protein, repp86, the exp ression of which is restricted to the cell cycle phases S, G(2), and M. The ratio of the 2 immunolabeling indices defines the rate of transition throu gh the restriction point. Telomerase activity was detected in 50 of 53 ECs (94%). Its levels correlated significantly with FIGO stage (P = .01) and FI GO grade (P = .003) but not with myometrial invasion. They were weakly asso ciated with the overall proliferative activity (Ki-67, r = .48) but signifi cantly with the repp86 index (r = .64) and even more strongly with the repp 86: Ki-67 ratio (r = .77). There was no correlation with mean telomere leng th. In the group of tumors with high telomerase activity, 5 patients had re lapses and 2 died of the disease within a median follow-up period of 29 mon ths. Recurrence showed no relation to FIGO grade and stage. No events were observed in the group with low telomerase activity. In a multivariate model including tumor stage, histopathologic grade, depth of myometrial invasion , and Ki-67 indices, telomerase activity emerged as the only independent pr edictor of disease progression (P = .0002). It is concluded that beyond a l ink to proliferation, high telomerase activity reflects a deregulation of t he cell cycle associated with an increased rate of cells entering S phase a nd a higher degree of malignancy. Therefore, quantitative analysis of telom erase activity may be useful for identifying EC patients at high risk for r ecurrence. Copyright (C) 2001 by W.B. Saunders Company.