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. Bigner, Yuchen Jiao (), Matthew S. Waitkus (), Alan K. Meeker () and Hai Yan ()
Additional contact information
Bill H. Diplas: Duke University Medical Center
Xujun He: Duke University Medical Center
Jacqueline A. Brosnan-Cashman: Johns Hopkins University School of Medicine
Heng Liu: Duke University Medical Center
Lee H. Chen: Duke University Medical Center
Zhaohui Wang: Duke University Medical Center
Casey J. Moure: Duke University Medical Center
Patrick J. Killela: Duke University Medical Center
Daniel B. Loriaux: Duke University Medical Center
Eric S. Lipp: Duke University Medical Center
Paula K. Greer: Duke University Medical Center
Rui Yang: Duke University Medical Center
Anthony J. Rizzo: Johns Hopkins University School of Medicine
Fausto J. Rodriguez: Johns Hopkins University School of Medicine
Allan H. Friedman: Duke University Medical Center
Henry S. Friedman: Duke University Medical Center
Sizhen Wang: Genetron Health (Beijing) Co. Ltd
Yiping He: Duke University Medical Center
Roger E. McLendon: Duke University Medical Center
Darell D. Bigner: Duke University Medical Center
Yuchen Jiao: National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Matthew S. Waitkus: Duke University Medical Center
Alan K. Meeker: Johns Hopkins University School of Medicine
Hai Yan: Duke University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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 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.

Date: 2018
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DOI: 10.1038/s41467-018-04448-6

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