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

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 (TP53WT) 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 H3.3K27M 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.

• Authors: Frank P B Dubois, Ofer Shapira, Noah F Greenwald, Travis Zack, Jeremiah Wala, Jessica W Tsai, Alexander Crane, Audrey Baguette, Djihad Hadjadj, Ashot S Harutyunyan, Kiran H Kumar, Mirjam Blattner-Johnson, Jayne Vogelzang, Cecilia Sousa, Kyung Shin Kang, Claire Sinai, Dayle K Wang, Prasidda Khadka, Kathleen Lewis, Lan Nguyen, Hayley Malkin, Patricia Ho, Ryan O'Rourke, Shu Zhang, Rose Gold, Davy Deng, Jonathan Serrano, Matija Snuderl, Chris Jones, Karen D Wright, Susan N Chi, Jacques Grill, Claudia L Kleinman, Liliana C Goumnerova, Nada Jabado, David T W Jones, Mark W Kieran, Keith L Ligon, Rameen Beroukhim, Pratiti Bandopadhayay
• Journal: Nature cancer (Nat Cancer) Vol. 3 Issue 8 Pg. 994-1011 (08 2022) ISSN: 2662-1347 [Electronic] England
• PMID: 35788723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Cell Cycle Proteins
• Histones
• MDM4 protein, human
• Proto-Oncogene Proteins

Topics

• Brain Neoplasms (genetics)
• Cell Cycle Proteins (genetics)
• Child
• Glioma (genetics)
• Histones (genetics)
• Humans
• Mutation
• Proto-Oncogene Proteins (genetics)