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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftJournal of Neuro-Oncology
ISSN1573-7373
DOI
StatusUdgivet - 2020

Fingeraftryk

Telomere Homeostasis
Isocitrate Dehydrogenase
Telomere
Maintenance
Mutation
Glioma
Down-Regulation
Cell Line
Doxycycline

Citer dette

@article{e48af04565c84c52a0eabb6fad8ab5a7,
title = "Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation",
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.",
keywords = "ALT, ATRX, D2HG, Isocitrate dehydrogenase, Q-FISH, TERT promoter, Telomerase, Telomere length",
author = "Ferreira, {Monica Sofia Ventura} and S{\o}rensen, {Mia Dahl} and Stefan Pusch and Dagmar Beier and Anne-Sophie Bouillon and Kristensen, {Bjarne Winther} and Br{\"u}mmendorf, {Tim Henrik} and Beier, {Christoph Patrick} and Fabian Beier",
year = "2020",
doi = "10.1007/s11060-020-03394-y",
language = "English",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Springer",

}

Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation. / Ferreira, Monica Sofia Ventura; Sørensen, Mia Dahl; Pusch, Stefan; Beier, Dagmar; Bouillon, Anne-Sophie; Kristensen, Bjarne Winther; Brümmendorf, Tim Henrik; Beier, Christoph Patrick; Beier, Fabian.

I: Journal of Neuro-Oncology, 2020.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation

AU - Ferreira, Monica Sofia Ventura

AU - Sørensen, Mia Dahl

AU - Pusch, Stefan

AU - Beier, Dagmar

AU - Bouillon, Anne-Sophie

AU - Kristensen, Bjarne Winther

AU - Brümmendorf, Tim Henrik

AU - Beier, Christoph Patrick

AU - Beier, Fabian

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - ALT

KW - ATRX

KW - D2HG

KW - Isocitrate dehydrogenase

KW - Q-FISH

KW - TERT promoter

KW - Telomerase

KW - Telomere length

U2 - 10.1007/s11060-020-03394-y

DO - 10.1007/s11060-020-03394-y

M3 - Journal article

JO - Journal of Neuro-Oncology

JF - Journal of Neuro-Oncology

SN - 0167-594X

ER -