The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma.

Published online

Journal 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 TERTpWT-IDHWT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTpWT-IDHWT 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 (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1.

Full Text

Duke Authors

Cited Authors

  • Diplas, BH; He, X; Brosnan-Cashman, JA; Liu, H; Chen, LH; Wang, Z; Moure, CJ; Killela, PJ; Loriaux, DB; Lipp, ES; Greer, PK; Yang, R; Rizzo, AJ; Rodriguez, FJ; Friedman, AH; Friedman, HS; Wang, S; He, Y; McLendon, RE; Bigner, DD; Jiao, Y; Waitkus, MS; Meeker, AK; Yan, H

Published Date

  • May 25, 2018

Published In

Volume / Issue

  • 9 / 1

Start / End Page

  • 2087 -

PubMed ID

  • 29802247

Pubmed Central ID

  • 29802247

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-04448-6


  • eng

Conference Location

  • England