Telomere biology in neuroblastoma: telomere binding proteins and alternative strengthening of telomeres

Purpose: Neuroblastoma (NBL) shows remarkable biologic heterogeneity, resulting in favorable or unfavorable prognoses. Previously, we reported that most unfavorable NBLs express high telomerase activity to maintain telomere length. Recently, telomere binding proteins (TBPs) and alternative lengthening of telomeres (ALTs) have been identified as key factors of telomere maintenance. Methods: To evaluate the correlation between telomerase activity, telomere length, and the expression levels of TBPs in NBL, we analyzed and quantified these factors in 121 untreated NBLs. Results: Shortened and elongated telomeres were detected in 21 (17.3%) and 11 cases (9.0%), respectively, and there was a significant correlation between telomere length and the length of the 3'-overhang. The tumors with shortened or elongated telomeres showed significant lower expression of TBPs, except for RAP1. Although telomerase activity did not correlate with telomere length, 16 of 22 cases with high telomerase activity and 5 of 9 cases (ALT tumors) that showed long telomeres without high telomerase activity resulted in death. High-dose chemotherapy did not have much effect on these deceased ALT cases, but their survival periods were more than 2 years and relatively long compared with the deceased cases with nonelongated telomeres, suggesting that chemoresistance in ALT tumors may be related to slow growth rates. Conclusions: High telomerase activity is a poor prognostic factor in NBL. In the cases without high telomerase activity, those with elongated telomere also showed poor outcomes because of chemoresistance. Therefore, ALT and TBPs may be biomarkers for chemosensitivity in NBL. Thus, a better understanding of telomere biology may help define the characteristics of individual NBLs. (C) 2009 Elsevier Inc. All rights reserved.