The clinical relevance of telomerase activity and telomere length in pediatric solid tumors

Abstract

8547 Background: Maintenance of telomeres, in the majority of cases by reactivation of telomerase, is obligatory for the indefinite proliferation of tumor cells. In some tumors, telomeres are maintained by a telomerase independent mechanism known as alternative lengthening of telomeres (ALT). Telomerase activity (TA) has been already established as a prognostic marker in adult and pediatric malignancies, but the clinical significance of telomere length (TRF) has not been yet determined. Methods: TA (TRAP analysis) and TRF (southern blotting) were evaluated in pediatric solid tumors: neuroblastoma (NBL), Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) and correlated to progression and prognosis. Results: High TA was detected in 52% (26/50) of NBL, 71% (15/21) ES and 40% (6/15) RMS primary tumors. In NBL a significant correlation between TA and outcome was detected (p=0.006) at diagnosis. In ES, 88 PBL samples were analyzed for minimal residual disease by TA during a long follow up (median 60 months). Highly significant association was observed between high TA and subsequent relapse (p>0.0001), predicting relapse before overt clinical progression. Shorter telomeres were detected in 46% (18/39) NBL and correlated with favorable prognosis (p=0.01). In the group of patients over one year of age, TA and TRF, each individually, defined two prognostic groups with favorable and adverse outcome. By multivariate analysis of known prognostic factors, TRF remained the only independent predictive variable. In RMS, preliminary results suggest that ALT is the predominant mechanism of telomere maintenance in embryonal RMS, while in alveolar RMS both telomerase dependent mechanism and ALT may be prevalent, reflecting the difference in prognosis in the two subgroups. Conclusions: Low and high TA were found to be of significant favorable and adverse prognosis, respectively, in NBL at diagnosis and in ES during follow up. Telomere length is a strong prognostic parameter in NBL patients, particularly in children older than one year. We recommend to include TA and TRF analyzes in the diagnostic investigations of NBL and ES. No significant financial relationships to disclose.