2026-08-13T07:15:26Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/252982024-11-29T13:12:37Zcom_20.500.12105_2273com_20.500.12105_2202col_20.500.12105_19571

00925njm 22002777a 4500 dc Montero-Conde, Cristina author Leandro-García, Luis Javier author Martínez-Montes, Ángel M author Martínez, Paula author Moya, Francisco J author Letón, Rocío author Gil, Eduardo author Martínez-Puente, Natalia author Guadalix, Sonsoles author Currás-Freixes, Maria author García-Tobar, Laura author Zafon, Carles author Jordà, Mireia author Riesco-Eizaguirre, Garcilaso author González-García, Patricia author Monteagudo, María author Torres-Pérez, Rafael author Mancikova, Veronika author Ruiz-Llorente, Sergio author Pérez-Martínez, Manuel author Pita, Guillermo author Galofré, Juan Carlos author Gonzalez-Neira, Anna author Cascón, Alberto author Rodríguez-Antona, Cristina author Megías, Diego author Blasco, MA author Caleiras, Eduardo author Robledo Batanero, Mercedes author Rodriguez Perales, Sandra author Montero-Conde, Cristina author Leandro-García, Luis Javier author Martínez-Montes, Ángel M author Martínez, Paula author Moya, Francisco J author Letón, Rocío author Gil, Eduardo author Martínez-Puente, Natalia author Guadalix, Sonsoles author Currás-Freixes, Maria author García-Tobar, Laura author Zafon, Carles author Jordà, Mireia author Riesco-Eizaguirre, Garcilaso author González-García, Patricia author Monteagudo, María author Torres-Pérez, Rafael author Mancikova, Veronika author Ruiz-Llorente, Sergio author Pérez-Martínez, Manuel author Pita, Guillermo author Galofré, Juan Carlos author Gonzalez-Neira, Anna author Cascón, Alberto author Rodríguez-Antona, Cristina author Megías, Diego author Caleiras, Eduardo author 2022-08 Comprehensive 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. Clin Transl Med . 2022 Aug;12(8):e1001. Clinical and Translational Medicine 35979662 https://hdl.handle.net/20.500.12105/25298 5p-end FISH TERC TERT promoter methylation TERT promoter mutation subtelomeric gene expression telomere shortening Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers.