Structural variants shape driver combinations and outcomes in pediatric high-grade glioma

Abstract

Pediatric high-grade gliomas (pHGGs), encompassing hemispheric and diffuse midline gliomas (DMGs), remain a devastating disease. The last decade has revealed oncogenic drivers including single nucleotide variants (SNVs) in histones. However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored due to limitations in early SV analysis approaches. Using SV algorithms, we recently created, we analyzed SVs in whole-genome sequences of 179 pHGGs including a novel cohort of treatment naïve samples–the largest WGS cohort assembled in adult or pediatric glioma. The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases, including a novel SV amplifying a MYC enhancer in the lncRNA CCDC26 in 12% of DMGs and revealing a more central role for MYC in these cancers than previously known. Applying de novo SV signature discovery, we identified five signatures including three (SVsig1-3) involving primarily simple SVs, and two (SVsig4-5) involving complex, clustered SVs. These SV signatures associated with genetic variants that differed from what was observed for SV signatures in other cancers, suggesting different links to underlying biology. Tumors with simple SV signatures were TP53 wild-type but were enriched with alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A, and RB1 early in tumor evolution, and with extrachromosomal amplicons that likely occurred later. All pHGGs exhibited at least one simple SV signature but complex SV signatures were primarily restricted to subsets of H3.3K27M DMGs and hemispheric pHGGs. Importantly, DMGs with the complex SV signatures SVsig4-5 were associated with shorter overall survival independent of histone type and TP53 status. These data inform the role and impact of SVs in gliomagenesis and mechanisms that shape them.

Dual Targeting of Histone Deacetylases and MYC as Potential Treatment Strategy for H3-K27M Pediatric Gliomas

“…1F), suggesting higher sensitivity of H3-K27M mutant cells to MYC inhibition by Sulfopin. These results are in line with previous reports showing H3-K27M-dependent activation of the MYC/RAS axis in mouse and human cells 12,23,24 . Of note, DMG cells showed greater sensitivity to the inhibitor compared to human astrocytic-like cells (Fig.…”

“…While PIN1 is not overexpressed in DMG tumors, we show that Sulfopin, although not inhibiting MYC directly, downregulates MYC target genes in patient-derived DMG cells and affects cell survival in a H3-K27M-dependant manner. These results are in line with the contribution of MYC signaling to H3-K27M-driven tumorigenesis 23,24 , underscoring the therapeutic potential of Sulfopin for these aggressive brain tumors. Notably, despite a significant reduction in tumor size in-vivo, the combined treatment did not increase mice survival.…”

“…High-level gene amplification of MYC is recurrently observed in pediatric high-grade gliomas 21,22 . H3-K27M gliomas show high expression of MYC and MYC target genes, due to both epigenetic alterations and structural variants, resulting in a viability dependency on MYC signaling 12,23,24 . Unfortunately, directly targeting MYC in tumors is extremely challanging 25…”

Genomic sequence context differs between germline and somatic structural variants allowing for their differentiation in tumor samples without paired normals

“…Due to their wide span, SV can affect multiple genes and up to a third of the average cancer genome 7 . SV can also alter the activity of distant cancer genes in multiple complex ways 8,9 . Thus, SVs can affect the cancer genome at least as profoundly as SNVs.…”