Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors

Anticancer Res. 2015 Jun;35(6):3501-10.


Telomere lengths in normal human cells are tightly regulated within a narrow range. Telomere length abnormalities are prevalent genetic alterations in malignant transformation. We studied telomere length abnormalities, telomerase RNA component (TERC) expression, alpha-thalassemia X-linked mental retardation (ATRX) expression, and death domain-associated protein (DAXX) expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We used tissue microarrays to perform telomere fluorescent in situ hybridization (FISH) and TERC in situ hybridization in 327 formalin-fixed paraffin-embedded tissues of GEP-NETs. Telomere length abnormalities were detected in 35% of 253 informative cases by using telomere FISH. Ten cases had altered lengthening of telomeres (ALT), an ALT-positive phenotype (4%), and 79 cases had telomere shortening (31%). The ALT-positive phenotype was significantly associated with tumors of pancreatic origin (7/10) and loss of ATRX or DAXX protein (8/10). Telomere shortening was significantly associated with low TERC expression. In the survival analysis, loss of ATRX or DAXX protein was associated with a decreased overall survival. Multivariate regression analysis showed that lymph node metastasis and high TERC expression were independent prognostic factors of reduced overall survival (OS) for patients with GEP-NETs. Our results showed that telomere lengthening (the ALT-positive phenotype) and telomere shortening accompanied by low TERC levels are two types of clinically significant telomere abnormalities in GEP-NETs.

Keywords: ATRX; DAXX; TERC; Telomere shortening; altered lengthening of telomeres; hybridization; immunohistochemistry; in situ; telomerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Co-Repressor Proteins
  • DNA Helicases / biosynthesis
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Situ Hybridization, Fluorescence
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / pathology
  • Male
  • Middle Aged
  • Molecular Chaperones
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / pathology
  • Nuclear Proteins / biosynthesis
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Prognosis*
  • RNA / biosynthesis*
  • RNA / genetics
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Telomerase / biosynthesis*
  • Telomerase / genetics
  • Telomere Shortening / genetics*
  • X-linked Nuclear Protein


  • Adaptor Proteins, Signal Transducing
  • Co-Repressor Proteins
  • DAXX protein, human
  • Molecular Chaperones
  • Nuclear Proteins
  • telomerase RNA
  • RNA
  • Telomerase
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein

Supplementary concepts

  • Gastro-enteropancreatic neuroendocrine tumor