Description:
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Purpose</jats:title>
<jats:p>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.
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<jats:title>Methods</jats:title>
<jats:p>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<jats:sup>R132H</jats:sup> mutation and CS-TL was studied in vitro using an IDH1<jats:sup>R132H</jats:sup> doxycycline-inducible glioma cell line system.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>Virtually all ALT<jats:sup>positive</jats:sup> astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALT<jats:sup>positive</jats:sup> samples had IDH1<jats:sup>R132H</jats:sup> mutations, resulting in a significantly longer CS-TL of IDH1<jats:sup>R132H</jats:sup> gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDH<jats:sup>wildtype</jats:sup>, 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<jats:sup>R132H</jats:sup> in the glioma cell line LN319 resulted in downregulation of ATRX and rapid TERT-independent telomere lengthening consistent with ALT.
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<jats:title>Conclusion</jats:title>
<jats:p>ALT is the major telomere maintenance mechanism in IDH<jats:sup>R132H</jats:sup> mutated astrocytomas, while TERT promoter mutations were associated with IDH<jats:sup>wildtype</jats:sup> glioma. IDH1<jats:sup>R132H</jats:sup> downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1<jats:sup>R132H</jats:sup> mutations, ATRX loss, and ALT.
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