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

Abstract

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.

A microdeletion event at 19q13.43 in IDH-mutant astrocytomas is strongly correlated with MYC overexpression

“…2). These findings may indicate to variations in oncogenic processes among IDH-mutant astrocytomas [28] Further analysis into the "WT" group revealed a subset of 21 tumours which had 42 genes with their expression inversely correlated with MYC expression. All of these 42 genes had copy number losses and were localized to 19q.…”

“…Next, we assessed the associations of these alterations with various genomic instability metrics. These metrics, which we devised and described previously, were used to characterise various aspects of genomic instability, including SNV burden, Insertion/Deletion (InDel) burden, copy-number alteration frequency (wGII: weighted Genomic Instability Index), degree of aneuploidy (CAER: chromosomal arm event ratio), copy-number amplitude, and chromothripsis status [28].…”

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma

“…PA usually exhibit +1q, −11q and −16q as well as +4q, and generally harbour considerably fewer CNVs than adults 88 . A study looking at the correlation of contributing factors of mutational burden in LGG and HGG showed that CNVs and loss of heterozygosity (LOH) clustered together, distinct from molecular alterations, suggesting that these changes may have a common lineage 89 . Research on CNVs are hence much needed to further our understanding of these alterations and the clinical impact they have on the pathogenesis of pA.…”

Opposed Interplay between IDH1 Mutations and the WNT/β-Catenin Pathway: Added Information for Glioma Classification

“…Mutations in enzymes regulating metabolite flux are implicated in gliomas development, as highlighted by the discovery of isocitrate dehydrogenase 1 (IDH1), in more than 70% of diffusely infiltrating WHO grade II and grade III astrocytic and oligodendroglial gliomas, as well as in a small fraction of glioblastomas (GBM), particularly those that develop from low-grade-gliomas (LGG) [3,[5][6][7][8].…”