Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation

Monica Sofia Ventura Ferreira, Mia Dahl Sørensen, Stefan Pusch, Dagmar Beier, Anne-Sophie Bouillon, Bjarne Winther Kristensen, Tim Henrik Brümmendorf, Christoph Patrick Beier, Fabian Beier

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Abstract

Purpose: Isocitrate dehydrogenase 1 (IDH1) mutations are associated with improved survival in gliomas. Depending on the IDH1 status, TERT promoter mutations affect prognosis. IDH1 mutations are associated with alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations and alternative lengthening of telomeres (ALT), suggesting an interaction between IDH1 and telomeres. However, little is known how IDH1 mutations affect telomere maintenance. Methods: We analyzed cell-specific telomere length (CS-TL) on a single cell level in 46 astrocytoma samples (WHO II-IV) by modified immune-quantitative fluorescence in situ hybridization, using endothelial cells as internal reference. In the same samples, we determined IDH1/TERT promoter mutation status and ATRX expression. The interaction of IDH1 R132H mutation and CS-TL was studied in vitro using an IDH1 R132H doxycycline-inducible glioma cell line system. Results: Virtually all ALT positive astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALT positive samples had IDH1 R132H mutations, resulting in a significantly longer CS-TL of IDH1 R132H gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDH wildtype, ATRX expression, lack of ALT and short CS-TL. ALT, TERT promoter mutations, and CS-TL remained without prognostic significance, when correcting for IDH1 status. In vitro, overexpression of IDH R132H in the glioma cell line LN319 resulted in downregulation of ATRX and rapid TERT-independent telomere lengthening consistent with ALT. Conclusion: ALT is the major telomere maintenance mechanism in IDH R132H mutated astrocytomas, while TERT promoter mutations were associated with IDH wildtype glioma. IDH1 R132H downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1 R132H mutations, ATRX loss, and ALT.

Original languageEnglish
JournalJournal of Neuro-Oncology
Volume147
Issue number1
Pages (from-to)1-14
ISSN1573-7373
DOIs
Publication statusPublished - Mar 2020

Keywords

  • ALT
  • ATRX
  • D2HG
  • Isocitrate dehydrogenase
  • Q-FISH
  • TERT promoter
  • Telomerase
  • Telomere length

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