Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma

J Clin Endocrinol Metab. 2014 Aug;99(8):E1571-9. doi: 10.1210/jc.2014-1158. Epub 2014 Apr 23.

Abstract

Context: Telomere maintenance via telomerase activation and the alternative lengthening of telomeres (ALT) mechanism was assessed in medullary thyroid carcinoma.

Setting and design: In total, 42 medullary thyroid carcinomas (MTC) were studied including 24 rearranged during transfection (RET)- mutated cases. Relative telomerase reverse transcriptase (TERT) expression, splice forms, and telomere length were determined by PCR-based methods, and telomerase activity by ELISA. The ALT mechanism was detected by Southern blot analysis and immunofluorescence.

Results: TERT expression and telomerase activity were detected in 21/42 tumors (50%), and was independent of the common somatic M918T RET mutation. Mean telomere length was shorter in MTCs compared with thyroids. Telomerase activation was associated with large tumor size (P = .027), advanced clinical stage (P = .0001), and short survival (P = .0001). Full-length TERT and the α(-) and β(-)-deletion forms were revealed, and the full-length form was associated with short survival (P = .04). A subset of cases without telomerase activation showed involvement of the ALT mechanism, which was associated with a low MIB-1 proliferation index (P = .024).

Conclusions: Stabilization of telomeres by telomerase activation occurs in half of the MTCs and by the ALT mechanism in a subset of cases. Telomerase activation may be used as an additional prognostic marker in medullary thyroid carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Neuroendocrine
  • DNA Mutational Analysis
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Male
  • Middle Aged
  • Prognosis
  • Proto-Oncogene Proteins c-ret / genetics
  • Survival Analysis
  • Telomerase / genetics*
  • Telomere / metabolism
  • Telomere Homeostasis / genetics*
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / mortality*
  • Thyroid Neoplasms / pathology
  • Young Adult

Substances

  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Telomerase

Supplementary concepts

  • Thyroid cancer, medullary