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 Keith Meeker, Hai Yan

Research output: Contribution to journalArticle

Abstract

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 (US)
Article number2087
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

telomeres
Isocitrate Dehydrogenase
dehydrogenases
Glioblastoma
Telomere Homeostasis
mutations
subgroups
phenotype
Telomerase
Mutation
Phenotype
Telomere
maintenance
Chemical activation
Maintenance
activation
biomarkers
Biomarkers
upstream
Tumors

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Diplas, B. H., He, X., Brosnan-Cashman, J. A., Liu, H., Chen, L. H., Wang, Z., ... Yan, H. (2018). The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma. Nature Communications, 9(1), [2087]. https://doi.org/10.1038/s41467-018-04448-6

The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma. / Diplas, Bill H.; He, Xujun; Brosnan-Cashman, Jacqueline A.; Liu, Heng; Chen, Lee H.; Wang, Zhaohui; Moure, Casey J.; Killela, Patrick J.; Loriaux, Daniel B.; Lipp, Eric S.; Greer, Paula K.; Yang, Rui; Rizzo, Anthony J.; Rodriguez, Fausto J; Friedman, Allan H.; Friedman, Henry S.; Wang, Sizhen; He, Yiping; McLendon, Roger E.; Bigner, Darell D.; Jiao, Yuchen; Waitkus, Matthew S.; Meeker, Alan Keith; Yan, Hai.

In: Nature Communications, Vol. 9, No. 1, 2087, 01.12.2018.

Research output: Contribution to journalArticle

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 2018, 'The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma', Nature Communications, vol. 9, no. 1, 2087. https://doi.org/10.1038/s41467-018-04448-6
Diplas BH, He X, Brosnan-Cashman JA, Liu H, Chen LH, Wang Z et al. The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma. Nature Communications. 2018 Dec 1;9(1). 2087. https://doi.org/10.1038/s41467-018-04448-6
Diplas, Bill H. ; He, Xujun ; Brosnan-Cashman, Jacqueline A. ; Liu, Heng ; Chen, Lee H. ; Wang, Zhaohui ; Moure, Casey J. ; Killela, Patrick J. ; Loriaux, Daniel B. ; Lipp, Eric S. ; Greer, Paula K. ; Yang, Rui ; Rizzo, Anthony J. ; Rodriguez, Fausto J ; Friedman, Allan H. ; Friedman, Henry S. ; Wang, Sizhen ; He, Yiping ; McLendon, Roger E. ; Bigner, Darell D. ; Jiao, Yuchen ; Waitkus, Matthew S. ; Meeker, Alan Keith ; Yan, Hai. / The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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