Scientific publications
Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers
Cristina Montero-Conde 1 2 , Luis Javier Leandro-García 1 , Ángel M Martínez-Montes 1 , Paula Martínez 3 , Francisco J Moya 4 , Rocío Letón 1 , Eduardo Gil 1 , Natalia Martínez-Puente 1 2 , Sonsoles Guadalix 5 , Maria Currás-Freixes 6 7 , Laura García-Tobar 8 , Carles Zafon 9 , Mireia Jordà 10 , Garcilaso Riesco-Eizaguirre 11 12 , Patricia González-García 13 , María Monteagudo 1 , Rafael Torres-Pérez 1 14 , Veronika Mancikova 1 , Sergio Ruiz-Llorente 15 , Manuel Pérez-Martínez 16 , Guillermo Pita 17 , Juan Carlos Galofré 18 19 , Anna Gonzalez-Neira 2 17 , Alberto Cascón 1 2 , Cristina Rodríguez-Antona 1 2 , Diego Megías 16 , María A Blasco 3 , Eduardo Caleiras 13 , Sandra Rodríguez-Perales 4 , Mercedes Robledo 1 2
Background: Comprehensive molecular studies on tumours are needed to delineate immortalization process steps and identify sensitive prognostic biomarkers in thyroid cancer.
Methods and results: 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.
Conclusions: Overall, our findings support that telomere shortening leads to a 5p subtelomeric region reorganization, facilitating the transcription and accumulation of alterations at TERT-locus.
CITATION Clin Transl Med. 2022 Aug;12(8):e1001. doi: 10.1002/ctm2.1001