Article (Scientific journals)
Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation.
Ferreira, Monica Sofia Ventura; Sorensen, Mia Dahl; Pusch, Stefan et al.
2020In Journal of Neuro-Oncology, 147 (1), p. 1-14
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Keywords :
ALT; ATRX; D2HG; Isocitrate dehydrogenase; Q-FISH; TERT promoter; Telomerase; Telomere length
Abstract :
[en] 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.
Disciplines :
Hematology
Author, co-author :
Ferreira, Monica Sofia Ventura
Sorensen, Mia Dahl
Pusch, Stefan
Beier, Dagmar
Bouillon, Anne-Sophie ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
Kristensen, Bjarne Winther
Brummendorf, Tim Henrik
Beier, Christoph Patrick
Beier, Fabian
Language :
English
Title :
Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation.
Publication date :
2020
Journal title :
Journal of Neuro-Oncology
ISSN :
0167-594X
eISSN :
1573-7373
Publisher :
Kluwer Academic Publishers, Netherlands
Volume :
147
Issue :
1
Pages :
1-14
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 22 April 2020

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