Scientific publications

Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers

Aug 1, 2022 | Magazine: Clinical and Translational Medicine

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