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oai:repisalud.isciii.es:20.500.12105/252982024-11-29T13:12:37Zcom_20.500.12105_2273com_20.500.12105_2202col_20.500.12105_19571
Repisalud 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 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 funder Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) funder Instituto de Salud Carlos III funder Comunidad de Madrid (España) funder Fundación La Caixa funder Banco Santander funder Asociación Española Contra el Cáncer 2024-10-25T10:42:26Z 2024-10-25T10:42:26Z 2022-08 Clin Transl Med . 2022 Aug;12(8):e1001. Clinical and Translational Medicine 35979662 https://hdl.handle.net/20.500.12105/25298 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. eng 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. research article 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 URL https://repisalud.isciii.es/bitstreams/49d7661b-ab84-430b-b91f-06cd33989ad2/download File MD5 0522c221a15155febeb329bb1437e30d 4775150 application/pdf Comprehensivemolecularanalysis-20222.pdf URL https://repisalud.isciii.es/bitstreams/ae097cfc-1466-44e0-addb-9709323efb6e/download File MD5 97991c643bec3614d87cd3e3071dfbfe 99107 text/plain Comprehensivemolecularanalysis-20222.pdf.txt