Detection of the alternative lengthening of telomeres pathway in malignant gliomas for improved molecular diagnosis

J Neurooncol. 2017 Nov;135(2):381-390. doi: 10.1007/s11060-017-2585-7. Epub 2017 Jul 28.

Abstract

Human malignant gliomas exhibit acquisition of either one of two telomere maintenance mechanisms, resulting from either reactivation of telomerase expression or activation of an alternative lengthening of telomeres (ALT) mechanism. In the present study, we analyzed 63 human malignant gliomas for the presence of ALT-specific extrachromosomal circles of telomeric DNA (C-circles) and measured telomerase expression, telomeric DNA content (Telo/Alu method), and telomeric repeat-containing RNAs (TERRA) levels. We also assessed histomolecular markers routinely used in clinical practice. The presence of C-circles significantly correlated with IDH1/2 mutation, MGMT exon 1 methylation, low Ki-67 immunostaining, increased telomeric DNA content, absence of functional ATRX protein and level of HTERT gene expression. In multivariate analysis, we observed a trend to a correlation between elevated TERRA levels and increased survival. Interestingly, the C-circles assay allowed to detect ALT activation in glioblastomas exhibiting wild-type IDH1/2 and ATRX expression. These results suggest that, after the correlations uncovered here have been confirmed on larger numbers of tumors, telomeric markers might be useful in improving diagnosis. They also point out to the utility of using the specific, sensitive and quantitative C-circle and Telo/Alu assays that can work with as few as 30 ng of tumor DNA.

Keywords: ATRX expression; Alternative lengthening of telomeres; C-circle assay; Gliomas; Telomeric markers.

MeSH terms

  • Adult
  • Brain / metabolism
  • Brain / pathology
  • Brain / surgery
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / surgery
  • Cell Line, Tumor
  • Cohort Studies
  • DNA Modification Methylases / genetics
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • Female
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology
  • Glioma / surgery
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Male
  • Middle Aged
  • Neoplasm Grading
  • RNA / metabolism
  • Telomerase / metabolism
  • Telomere Homeostasis* / physiology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • X-linked Nuclear Protein / metabolism

Substances

  • Tumor Suppressor Proteins
  • RNA
  • IDH2 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • DNA Modification Methylases
  • MGMT protein, human
  • TERT protein, human
  • Telomerase
  • ATRX protein, human
  • X-linked Nuclear Protein
  • DNA Repair Enzymes