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

Clin Transl Med. 2022 Aug;12(8):e1001. doi: 10.1002/ctm2.1001.


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.

Keywords: 5p-end FISH; TERC; TERT promoter methylation; TERT promoter mutation; subtelomeric gene expression; telomere shortening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • In Situ Hybridization, Fluorescence
  • Prognosis
  • Telomerase* / genetics
  • Telomerase* / metabolism
  • Telomere / genetics
  • Telomere / metabolism
  • Thyroid Neoplasms* / diagnosis
  • Thyroid Neoplasms* / genetics


  • Telomerase