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

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.