The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma

Academic Article


  • The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTp WT-IDH WT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTp WT-IDH WT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDH WT-TERT SV), and an ALT-positive subgroup (IDH WT-ALT) with mutations in ATRX or SMARCAL1.
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    Digital Object Identifier (doi)

    Author List

  • Diplas BH; He X; Brosnan-Cashman JA; Liu H; Chen LH; Wang Z; Moure CJ; Killela PJ; Loriaux DB; Lipp ES
  • Volume

  • 9
  • Issue

  • 1