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 H3.3 K27M 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.

The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location

“…Previously published WGS data of tumors ICGC-GBM27, ICGC-GBM96 and ICGC-GBM60 are deposited at EGA00001001139, and WGS data for BT836 and BT869 have been published under dbGaP accession number phs002380.v1.p1 (ref. 84 ). H3-K27M DMG ChIP-seq data were utilized from GSE126319 (ref.…”

SMARCB1 loss creates patient-specificMYCtopologies that drive malignant rhabdoid tumor growth

“…Collectively, we refer to these putative super enhancer regions as Rhabdoid Oncogenic MYC Enhancer (RhOME) and number them according to their position in the genome. Notably, in contrast to RhOME2, RhOME1 (PCAT1) and RhOME3 (CCDC26) were previously identified as MYC regulatory regions in other tumor entities [24][25][26] . Our Hi-C and 4C experiments thus revealed that in different MRT PDOs, distinct distal enhancers interacting with the MYC promoter are active (RhOME1-3).…”

Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

“…Raw mass-spectrometry data is available for download from https://massive.ucsd.edu/, accession numbers MSV000087736 (reviewer login: username, MSV000087736_reviewer; password, HISTH3_BioID) and MSV000089173 (reviewer login: username, MSV000089173_reviewer; password: H3_mutants). Whole genome sequencing data is available under EGAS00001000575, EGAS00001001139, EGAS00001000572, EGAS00001000192, and under dbGaP accession number phs002380.v1.p1 (Dubois et al, 2022). All other data are available in the main text or the supplemental information.…”