Structural variants shape driver combinations and outcomes in pediatric high-grade glioma.
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ICR Authors
Authors
Dubois, FPB
Shapira, O
Greenwald, NF
Zack, T
Wala, J
Tsai, JW
Crane, A
Baguette, A
Hadjadj, D
Harutyunyan, AS
Kumar, KH
Blattner-Johnson, M
Vogelzang, J
Sousa, C
Kang, KS
Sinai, C
Wang, DK
Khadka, P
Lewis, K
Nguyen, L
Malkin, H
Ho, P
O'Rourke, R
Zhang, S
Gold, R
Deng, D
Serrano, J
Snuderl, M
Jones, C
Wright, KD
Chi, SN
Grill, J
Kleinman, CL
Goumnerova, LC
Jabado, N
Jones, DTW
Kieran, MW
Ligon, KL
Beroukhim, R
Bandopadhayay, P
Shapira, O
Greenwald, NF
Zack, T
Wala, J
Tsai, JW
Crane, A
Baguette, A
Hadjadj, D
Harutyunyan, AS
Kumar, KH
Blattner-Johnson, M
Vogelzang, J
Sousa, C
Kang, KS
Sinai, C
Wang, DK
Khadka, P
Lewis, K
Nguyen, L
Malkin, H
Ho, P
O'Rourke, R
Zhang, S
Gold, R
Deng, D
Serrano, J
Snuderl, M
Jones, C
Wright, KD
Chi, SN
Grill, J
Kleinman, CL
Goumnerova, LC
Jabado, N
Jones, DTW
Kieran, MW
Ligon, KL
Beroukhim, R
Bandopadhayay, P
Document Type
Journal Article
Date
2022-06-01
Date Accepted
2022-05-23
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.
Citation
Nature Cancer, 2022, 3 (8), pp. 994 - 1011
Source Title
Nature Cancer
Publisher
OXFORD UNIV PRESS INC
ISSN
2662-1347
eISSN
2662-1347
2662-1347
2662-1347
Collections
Research Team
Glioma Team