1. The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma
- Author
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Henry S. Friedman, Alan K. Meeker, Yiping He, Fausto J. Rodriguez, Xujun He, Jacqueline A. Brosnan-Cashman, Roger E. McLendon, Rui Yang, Paula K. Greer, Daniel B. Loriaux, Allan H. Friedman, Matthew S. Waitkus, Yuchen Jiao, Patrick J. Killela, Darell D. Bigner, Lee H. Chen, Eric S. Lipp, Heng Liu, Casey J. Moure, Anthony J. Rizzo, Wang Sizhen, Hai Yan, Bill H. Diplas, and Zhaohui Wang
- Subjects
Adult ,Male ,0301 basic medicine ,Telomerase ,Adolescent ,Science ,General Physics and Astronomy ,Biology ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,Telomere Homeostasis ,Cell Line, Tumor ,medicine ,Humans ,lcsh:Science ,Promoter Regions, Genetic ,neoplasms ,ATRX ,Aged ,Aged, 80 and over ,Mutation ,Multidisciplinary ,Brain Neoplasms ,DNA Helicases ,Wild type ,Genomics ,General Chemistry ,Middle Aged ,Survival Analysis ,Phenotype ,Isocitrate Dehydrogenase ,Telomere ,nervous system diseases ,HEK293 Cells ,030104 developmental biology ,Isocitrate dehydrogenase ,Cancer research ,lcsh:Q ,Female ,Glioblastoma ,HeLa Cells - 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., Glioblastoma can be classified based on IDH and TERT promoter mutations, but ~20% of glioblastoma do not have these mutations (TERTpWT-IDHWT glioblastoma). Here, the authors present a genetic landscape of TERTpWT-IDHWT glioblastoma, identifying a telomerase-positive subgroup driven by TERT-structural rearrangements and an ALT-positive subgroup with mutations in ATRX or SMARCAL1.
- Published
- 2018