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Article

Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms

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Department of Biostatistics and Medical Informatics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
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Department of Medical Engineering, Faculty of Engineering, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
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Department of Genetics, School of Medicine, Yale University, New Haven, CT 06520, USA
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Yale Center for Genome Analysis, West Haven, CT 06516, USA
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Izmir Biomedicine and Genome Center (IBG), Izmir 35340, Turkey
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Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, Izmir 35340, Turkey
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Department of Medical Biology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
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Department of Pathology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
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Neuropathology Division, Department of Pathology, School of Medicine, University of California San Fransisco (UCSF), San Francisco, CA 94143, USA
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Department of Molecular Biology, School of Arts and Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
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Department of Neurosurgery, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
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Author to whom correspondence should be addressed.
Biomedicines 2020, 8(12), 574; https://doi.org/10.3390/biomedicines8120574
Received: 29 September 2020 / Revised: 27 October 2020 / Accepted: 3 November 2020 / Published: 7 December 2020
(This article belongs to the Special Issue Molecular and Pathological Mechanisms of Adult Gliomas)
Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and “Others” differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA. View Full-Text
Keywords: glioma; mutational signatures; DNA repair; exome sequencing glioma; mutational signatures; DNA repair; exome sequencing
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MDPI and ACS Style

Ülgen, E.; Karacan, S.; Gerlevik, U.; Can, Ö.; Bilguvar, K.; Oktay, Y.; B. Akyerli, C.; K. Yüksel, Ş.; E. Danyeli, A.; Tihan, T.; Sezerman, O.U.; Yakıcıer, M.C.; Pamir, M.N.; Özduman, K. Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms. Biomedicines 2020, 8, 574. https://doi.org/10.3390/biomedicines8120574

AMA Style

Ülgen E, Karacan S, Gerlevik U, Can Ö, Bilguvar K, Oktay Y, B. Akyerli C, K. Yüksel Ş, E. Danyeli A, Tihan T, Sezerman OU, Yakıcıer MC, Pamir MN, Özduman K. Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms. Biomedicines. 2020; 8(12):574. https://doi.org/10.3390/biomedicines8120574

Chicago/Turabian Style

Ülgen, Ege, Sıla Karacan, Umut Gerlevik, Özge Can, Kaya Bilguvar, Yavuz Oktay, Cemaliye B. Akyerli, Şirin K. Yüksel, Ayça E. Danyeli, Tarık Tihan, O. U. Sezerman, M. C. Yakıcıer, M. N. Pamir, and Koray Özduman. 2020. "Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms" Biomedicines 8, no. 12: 574. https://doi.org/10.3390/biomedicines8120574

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