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

Nat Cancer
Authors
Abstract

We analyzed the contributions of structural variants (SVs) to gliomagenesis across 179 pediatric high-grade gliomas (pHGGs). The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases (RTKs), including an SV amplifying a MYC enhancer in 12% of diffuse midline gliomas (DMG), indicating an underappreciated role for MYC in pHGG. SV signature analysis revealed that tumors with simple signatures were TP53 wild type (TP53) but showed 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 later-occurring extrachromosomal amplicons. All pHGGs exhibited at least one simple-SV signature, but complex-SV signatures were primarily restricted to subsets of H3.3 DMGs and hemispheric pHGGs. Importantly, DMGs with complex-SV signatures were associated with shorter overall survival independent of histone mutation and TP53 status. These data provide insight into the impact of SVs on gliomagenesis and the mechanisms that shape them.

Year of Publication
2022
Journal
Nat Cancer
Date Published
2022 Jul 04
ISSN
2662-1347
DOI
10.1038/s43018-022-00403-z
PubMed ID
35788723
Links
Grant list
R01 CA188228 / CA / NCI NIH HHS / United States
R01 CA215489 / CA / NCI NIH HHS / United States
R01 CA219943 / CA / NCI NIH HHS / United States
R01 CA188228 / CA / NCI NIH HHS / United States
R01 CA215489 / CA / NCI NIH HHS / United States
R01 CA219943 / CA / NCI NIH HHS / United States
R37 5R37CA255245-02 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)