GENE-42. THE GENOMIC LANDSCAPE OF TRIPLE-NEGATIVE GLIOBLASTOMA Article Swipe

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Bill H. Diplas , Matthew S. Waitkus , Xujun He , Jackie Brosnan-Cashman , Heng Liu , Lee Chen , Zhaohui Wang , Casey J. Moure , Patrick Killela , Eric Lipp , Fausto J. Rodríguez , Yuchen Jiao , Roger E. McLendon , Darell D. Bigner , Alan K. Meeker , Hai Yan ·

YOU? · · 2018 · Open Access · · DOI: https://doi.org/10.1093/neuonc/noy148.468

Glioblastoma (GBM) is the most common and deadly primary malignant brain tumor in adults. Mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH1/2) can classify ~80% of GBMs into molecular subgroups with distinct clinical courses. 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, approximately 20% of GBMs lack alterations in TERTp and IDH1/2. These tumors, designated TERTp(WT)-IDH(WT) or triple-negative glioblastomas (as they also lack 1p19q co-deletion) do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we performed whole-exome, whole-genome, and RNA-sequencing on a cohort of triple-negative GBMs to define their genetic landscape. We discovered recurrent inactivating mutations in SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) in 21% (8/39) of triple-negative GBMs. Using telomere maintenance characterization assays, we show that SMARCAL1-mutant cases exhibited the ALT phenotype. Using CRISPR/Cas9 gene editing in GBM cell lines, we found that inducing loss of SMARCAL1 generates features of ALT. Rescue of expression of SMARCAL1 in SMARCAL1-null cell lines markedly suppressed ALT features and was dependent on the enzyme helicase activity. Furthermore, using break-apart FISH and whole genome sequencing, we identified recurrent rearrangements upstream of TERT in ~50% of triple-negative GBMs. These TERT-rearranged tumors exhibited elevated levels of TERT mRNA expression. This represents a novel mechanism of telomerase activation in GBMs lacking the well-known TERT promoter hotspot mutations. Finally, we identify recurrent BRAF V600E mutations in younger patients with GBM. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDH(WT)-TERT(SV), ~50%), and an ALT-positive subgroup (IDH(WT)-ALT, ~40%) with mutations in ATRX or SMARCAL1. We also establish SMARCAL1 inactivating

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Biology Telomere ATRX Isocitrate dehydrogenase Telomerase Gene Mutation IDH1 Cancer research Phenotype Molecular biology Genetics Enzyme Biochemistry

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Type: article
Language: en
Landing Page: https://doi.org/10.1093/neuonc/noy148.468
PDF: https://academic.oup.com/neuro-oncology/article-pdf/20/suppl_6/vi112/26280959/noy148.468.pdf
OA Status: bronze
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DOI: https://doi.org/10.1093/neuonc/noy148.468

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Title: GENE-42. THE GENOMIC LANDSCAPE OF TRIPLE-NEGATIVE GLIOBLASTOMA

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Language: en

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Publication year: 2018

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Publication date: 2018-11-01

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Authors: Bill H. Diplas, Matthew S. Waitkus, Xujun He, Jackie Brosnan-Cashman, Heng Liu, Lee Chen, Zhaohui Wang, Casey J. Moure, Patrick Killela, Eric Lipp, Fausto J. Rodríguez, Yuchen Jiao, Roger E. McLendon, Darell D. Bigner, Alan K. Meeker, Hai Yan

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Landing page: https://doi.org/10.1093/neuonc/noy148.468

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Concepts: Biology, Telomere, ATRX, Isocitrate dehydrogenase, Telomerase, Gene, Mutation, IDH1, Cancer research, Phenotype, Molecular biology, Genetics, Enzyme, Biochemistry

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