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Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms
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 dif...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762325/ https://www.ncbi.nlm.nih.gov/pubmed/33297360 http://dx.doi.org/10.3390/biomedicines8120574 |
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author | Ülgen, Ege Karacan, Sıla Gerlevik, Umut Can, Özge Bilguvar, Kaya Oktay, Yavuz B. Akyerli, Cemaliye K. Yüksel, Şirin E. Danyeli, Ayça Tihan, Tarık Sezerman, O. Uğur Yakıcıer, M. Cengiz Pamir, M. Necmettin Özduman, Koray |
author_facet | Ülgen, Ege Karacan, Sıla Gerlevik, Umut Can, Özge Bilguvar, Kaya Oktay, Yavuz B. Akyerli, Cemaliye K. Yüksel, Şirin E. Danyeli, Ayça Tihan, Tarık Sezerman, O. Uğur Yakıcıer, M. Cengiz Pamir, M. Necmettin Özduman, Koray |
author_sort | Ülgen, Ege |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7762325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77623252020-12-26 Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms Ülgen, Ege Karacan, Sıla Gerlevik, Umut Can, Özge Bilguvar, Kaya Oktay, Yavuz B. Akyerli, Cemaliye K. Yüksel, Şirin E. Danyeli, Ayça Tihan, Tarık Sezerman, O. Uğur Yakıcıer, M. Cengiz Pamir, M. Necmettin Özduman, Koray Biomedicines Article 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. MDPI 2020-12-07 /pmc/articles/PMC7762325/ /pubmed/33297360 http://dx.doi.org/10.3390/biomedicines8120574 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ülgen, Ege Karacan, Sıla Gerlevik, Umut Can, Özge Bilguvar, Kaya Oktay, Yavuz B. Akyerli, Cemaliye K. Yüksel, Şirin E. Danyeli, Ayça Tihan, Tarık Sezerman, O. Uğur Yakıcıer, M. Cengiz Pamir, M. Necmettin Özduman, Koray Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms |
title | Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms |
title_full | Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms |
title_fullStr | Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms |
title_full_unstemmed | Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms |
title_short | Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms |
title_sort | mutations and copy number alterations in idh wild-type glioblastomas are shaped by different oncogenic mechanisms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762325/ https://www.ncbi.nlm.nih.gov/pubmed/33297360 http://dx.doi.org/10.3390/biomedicines8120574 |
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