The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma

Bill H. Diplas, Xujun He, Jacqueline A. Brosnan-Cashman, Heng Liu, Lee H. Chen, Zhaohui Wang, Casey J. Moure, Patrick J. Killela, Daniel B. Loriaux, Eric S. Lipp, Paula K. Greer, Rui Yang, Anthony J. Rizzo, Fausto J. Rodriguez, Allan H. Friedman, Henry S. Friedman, Sizhen Wang, Yiping He, Roger E. McLendon, Darell D. BignerYuchen Jiao, Matthew S. Waitkus, Alan K. Meeker, Hai Yan

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


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.

Original languageEnglish
Article number2087
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2018
Externally publishedYes


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