Endocrine Abstracts

Intracranial tumors (IT) comprise a heterogenous group of neoplasias (e.g., pituitary/brain tumors and craniopharyngiomas), characterized by difficult diagnosis based on MRI, challenging prognostic predictors and lack of effective therapeutic strategies. In addition, these tumors are usually associated with neurological disorders and severe comorbidities (e.g., those associated with Cushing syndrome, Acromegaly, etc.), worsening the quality life of patients. In this context, several elements of the telomerase/shelterin system, a macromolecular machinery responsible for maintenance of telomers and genomic stability, have been suggested to exert an important role in different endocrine IT (i.e., TERC in pituitary tumors, TERT promoter in craniopharyngiomas, and TRF1 in glioblastomas). However, the information about the presence, clinical relevance and potential functional role of the telomerase/shelterin system is still quite limited, fragmentary, and unclear in IT. Therefore, our aim was to extensively characterize the expression levels and clinical/functional relevance of the components of this system in endocrine IT. To that end, expression levels of 17 telomerase/shelterin components were analysed by microarray technology based on qPCR-methodology in different cohorts of IT vs. control samples: 1) Pituitary [10 Normal Pituitary (NPs) vs. 83 Non-Functioning Pituitary Tumors (NFPTs), 50 GHomas, 19 ACTHomas and 6 PRLomas samples], 2) Brain [7 Normal Brain (NBs) vs. 69 brain tumor samples], and 3) 60 Craniopharyngioma vs. NP/NB samples. Moreover, several bioinformatic analyses (PLSDA/heatmap/k-means clusterization) with molecular/clinical features, and different functional approaches [e.g., treatment with etoposide (telomerase inhibitor) in selected primary derived cell-cultures and cell line models] were performed. Results revealed an alteration of telomerase expression levels in brain-tumor vs. NB samples (e.g., TREF2IP and 4 splicing-variants of TERT gene were found to be downregulated in tumor samples, having a diagnostic/prognostic potential). Dysregulation of the telomerase/shelterin system was also observed in different pituitary-tumors vs. NPs, being some of these changes common across pathologies (i.e., TERF2, TREF2IP, and TINF2). Interestingly, two different subtypes in NFPTs and GHomas could be identified based on their telomerase/shelterin component profile reinforcing the heterogeneity of pituitary-tumors. A clear dysregulation of the telomerase/shelterin system was also observed in craniopharyngiomas, highlighting again the TERF2IP as a potential biomarker in this pathology. Finally, the antiproliferative effect of etoposide was dependent on the tumor type analysed. Altogether, our study revealed a profound dysregulation in the shelterin/telomerase complex in IT wherein some of the components might be clinically and functionally relevant, opening new avenues to improve the management of these pathologies.