| Literature DB >> 35788723 |
Frank P B Dubois1,2, Ofer Shapira1,2, Noah F Greenwald1,2, Travis Zack1,2, Jeremiah Wala1,2, Jessica W Tsai2,3,4, Alexander Crane1,2, Audrey Baguette5, Djihad Hadjadj6, Ashot S Harutyunyan6, Kiran H Kumar1,2, Mirjam Blattner-Johnson7,8, Jayne Vogelzang9, Cecilia Sousa9, Kyung Shin Kang1,2, Claire Sinai9, Dayle K Wang2,4, Prasidda Khadka1,2, Kathleen Lewis2, Lan Nguyen2, Hayley Malkin9, Patricia Ho1,2, Ryan O'Rourke1,2, Shu Zhang1,2, Rose Gold1,2, Davy Deng1,2, Jonathan Serrano10, Matija Snuderl10, Chris Jones11, Karen D Wright3,4, Susan N Chi3,4, Jacques Grill12, Claudia L Kleinman6,13, Liliana C Goumnerova14,15, Nada Jabado6,16, David T W Jones7,8, Mark W Kieran2,3,4,15, Keith L Ligon17,18,19,20, Rameen Beroukhim21,22,23, Pratiti Bandopadhayay24,25,26.
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.Entities:
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Year: 2022 PMID： 35788723 DOI： 10.1038/s43018-022-00403-z
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347