Monica Sofia Ventura Ferreira1, Mia Dahl Sørensen2,3, Stefan Pusch4,5,6, Dagmar Beier3,7, Anne-Sophie Bouillon1, Bjarne Winther Kristensen2,3, Tim Henrik Brümmendorf1, Christoph Patrick Beier3,7, Fabian Beier8. 1. Department of Haematology, Oncology, Medical Faculty, RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. 2. Department of Pathology, University Hospital Odense, Sdr. Boulevard 29, 5000, Odense, Denmark. 3. Department of Clinical Research, University of Southern Denmark, Sdr. Boulevard 29, 5000, Odense, Denmark. 4. Department of Neuropathology, University of Heidelberg, Heidelberg, Germany. 5. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. German Cancer Consortium (DKTK), Heidelberg, Germany. 7. Department of Neurology, University Hospital Odense, Sdr. Boulevard 29, 5000, Odense, Denmark. 8. Department of Haematology, Oncology, Medical Faculty, RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. fbeier@ukaachen.de.
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 IDH1R132H mutation and CS-TL was studied in vitro using an IDH1R132H doxycycline-inducible glioma cell line system. RESULTS: Virtually all ALTpositive astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALTpositive samples had IDH1R132H mutations, resulting in a significantly longer CS-TL of IDH1R132H gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDHwildtype, 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 IDHR132H 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 IDHR132H mutated astrocytomas, while TERT promoter mutations were associated with IDHwildtype glioma. IDH1R132H downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1R132H mutations, ATRX loss, and ALT.
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 IDH1R132H mutation and CS-TL was studied in vitro using an IDH1R132Hdoxycycline-inducible glioma cell line system. RESULTS: Virtually all ALTpositive astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALTpositive samples had IDH1R132H mutations, resulting in a significantly longer CS-TL of IDH1R132Hgliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDHwildtype, 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 IDHR132H 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 IDHR132H mutated astrocytomas, while TERT promoter mutations were associated with IDHwildtype glioma. IDH1R132H downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1R132H mutations, ATRX loss, and ALT.
Authors: Pavithra Viswanath; Georgios Batsios; Vinay Ayyappan; Céline Taglang; Anne Marie Gillespie; Peder E Z Larson; H Artee Luchman; Joseph F Costello; Russell O Pieper; Sabrina M Ronen Journal: Neuro Oncol Date: 2021-09-01 Impact factor: 13.029
Authors: Pavithra Viswanath; Georgios Batsios; Joydeep Mukherjee; Anne Marie Gillespie; Peder E Z Larson; H Artee Luchman; Joanna J Phillips; Joseph F Costello; Russell O Pieper; Sabrina M Ronen Journal: Nat Commun Date: 2021-01-04 Impact factor: 14.919
Authors: Danny MacKenzie; Andrea K Watters; Julie T To; Melody W Young; Jonathan Muratori; Marni H Wilkoff; Rita G Abraham; Maria M Plummer; Dong Zhang Journal: Cancers (Basel) Date: 2021-05-14 Impact factor: 6.639