Telomerase activation in small intestinal neuroendocrine tumours is associated with aberrant TERT promoter methylation, but not hot-spot mutations

Epigenetics. 2019 Dec;14(12):1224-1233. doi: 10.1080/15592294.2019.1634987. Epub 2019 Jul 19.


Telomere maintenance is a critical requirement for enabling replicative immortality and tumour development. Here, telomerase expression and activity, telomere length (TL) and potential regulatory factors that can underlie telomerase machinery alterations in small intestinal neuroendocrine tumours (SI-NETs) were analyzed. Telomerase activity assessed by TRAP assay was increased in SI-NETs compared to normal ileum (P < 0.001). The telomerase reverse transcriptase gene (TERT) was over-expressed in SI-NETs vs. normal ileal samples (P = 0.01). Furthermore, relative TL assessed by qPCR was found shorter in tumours compared with normal ileum (P = 0.02) and in distant metastasis samples compared to primary tumours and local metastases (P= 0.02). TERT promoter hotspot mutations were not present and TERT copy number gain was only observed in 3/70 tumour samples. TERT or chromosome 18 copy number alterations were not associated with telomerase expression and activity or TL. However, hypermethylation of TERT promoter in Region B - in the proximity of the transcription start site - was inversely correlated with TERT expression and telomerase activity and positively correlated with TL. Global LINE1 methylation was positively correlated with TERT promoter Region B methylation and was inversely correlated with telomerase activity, TERT expression and the upstream Region A methylation. The results show that telomerase activation, TERT expression and shorter telomeres are commonly found in SI-NETs. Aberrant DNA methylation of TERT promoter and of LINE1 can be implicated in abnormal regulation of TERT in SI-NETs.

Keywords: DNA methylation; SI-NET; TERT; Telomere; telomerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Methylation*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / metabolism
  • Long Interspersed Nucleotide Elements / genetics
  • Mutation
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / metabolism
  • Promoter Regions, Genetic
  • Telomerase / genetics*
  • Telomerase / metabolism
  • Telomere Homeostasis


  • TERT protein, human
  • Telomerase

Grants and funding

The study was supported by grants from the Swedish Cancer Society, the Cancer Society in Stockholm, the Gustav V Jubilee Foundation, Stockholm county council and Karolinska Institutet. This work was supported by the Cancerfonden [CAN 2017/571]; Cancerföreningen i Stockholm [161143]; Karolinska Institutet [There is no number.]; Stiftelsen Konung Gustaf V:s Jubileumsfond [174203]; Stockholms Läns Landsting [Dnr LS 1311-1460].