Montero-Conde, CristinaLeandro-García, Luis JavierMartínez-Montes, Ángel MMartínez, PaulaMoya, Francisco JLetón, RocíoGil, EduardoMartínez-Puente, NataliaGuadalix, SonsolesCurrás-Freixes, MariaGarcía-Tobar, LauraZafon, CarlesJordà, MireiaRiesco-Eizaguirre, GarcilasoGonzález-García, PatriciaMonteagudo, MaríaTorres-Pérez, RafaelMancikova, VeronikaRuiz-Llorente, SergioPérez-Martínez, ManuelPita, GuillermoGalofré, Juan CarlosGonzalez-Neira, AnnaCascón, AlbertoRodríguez-Antona, CristinaMegías, DiegoBlasco, MACaleiras, EduardoRobledo Batanero, MercedesRodriguez Perales, SandraMontero-Conde, CristinaLeandro-García, Luis JavierMartínez-Montes, Ángel MMartínez, PaulaMoya, Francisco JLetón, RocíoGil, EduardoMartínez-Puente, NataliaGuadalix, SonsolesCurrás-Freixes, MariaGarcía-Tobar, LauraZafon, CarlesJordà, MireiaRiesco-Eizaguirre, GarcilasoGonzález-García, PatriciaMonteagudo, MaríaTorres-Pérez, RafaelMancikova, VeronikaRuiz-Llorente, SergioPérez-Martínez, ManuelPita, GuillermoGalofré, Juan CarlosGonzalez-Neira, AnnaCascón, AlbertoRodríguez-Antona, CristinaMegías, DiegoCaleiras, Eduardo2024-10-252024-10-252022-08Clin Transl Med . 2022 Aug;12(8):e1001.https://hdl.handle.net/20.500.12105/25298Comprehensive molecular studies on tumours are needed to delineate immortalization process steps and identify sensitive prognostic biomarkers in thyroid cancer.In this study, we extensively characterize telomere-related alterations in a series of 106 thyroid tumours with heterogeneous clinical outcomes. Using a custom-designed RNA-seq panel, we identified five telomerase holoenzyme-complex genes upregulated in clinically aggressive tumours compared to tumours from long-term disease-free patients, being TERT and TERC denoted as independent prognostic markers by multivariate regression model analysis. Characterization of alterations related to TERT re-expression revealed that promoter mutations, methylation and/or copy gains exclusively co-occurred in clinically aggressive tumours. Quantitative-FISH (fluorescence in situ hybridization) analysis of telomere lengths showed a significant shortening in these carcinomas, which matched with a high proliferative rate measured by Ki-67 immunohistochemistry. RNA-seq data analysis indicated that short-telomere tumours exhibit an increased transcriptional activity in the 5-Mb-subtelomeric regions, site of several telomerase-complex genes. Gene upregulation enrichment was significant for specific chromosome-ends such as the 5p, where TERT is located. Co-FISH analysis of 5p-end and TERT loci showed a more relaxed chromatin configuration in short telomere-length tumours compared to normal telomere-length tumours.Overall, our findings support that telomere shortening leads to a 5p subtelomeric region reorganization, facilitating the transcription and accumulation of alterations at TERT-locus.engVoR5p-end FISHTERCTERT promoter methylationTERT promoter mutationsubtelomeric gene expressiontelomere shortening35979662128e1001Clinical and Translational Medicineopen access