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

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

doi:10.1038/s43018-022-00403-z

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

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 (Corresponding Author), Rameen Beroukhim (Corresponding Author), Pratiti Bandopadhayay (Corresponding Author)

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

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^WT) 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^K27M 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.

Original language	English
Pages (from-to)	994-1011
Number of pages	18
Journal	Nature Cancer
Volume	3
Issue number	8
DOIs	https://doi.org/10.1038/s43018-022-00403-z
Publication status	Published - Aug 2022
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords*

gliomas

Field of Science*

3.2 Clinical medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

Access to Document

10.1038/s43018-022-00403-z

Cite this

Dubois, F. P. B., Shapira, O., Greenwald, N. F., Zack, T., Wala, J., Tsai, J. W., Crane, A., Baguette, A., Hadjadj, D., Harutyunyan, A. S., Kumar, K. H., Blattner-Johnson, M., Vogelzang, J., Sousa, C., Kang, K. S., Sinai, C., Wang, D. K., Khadka, P., Lewis, K., ... Bandopadhayay, P. (2022). Structural variants shape driver combinations and outcomes in pediatric high-grade glioma. Nature Cancer, 3(8), 994-1011. https://doi.org/10.1038/s43018-022-00403-z

@article{1120e4a061a54a4996e052406de45520,

title = "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.",

keywords = "gliomas",

author = "Dubois, \{Frank P.B.\} and Ofer Shapira and Greenwald, \{Noah F.\} and Travis Zack and Jeremiah Wala and Tsai, \{Jessica W.\} and Alexander Crane and Audrey Baguette and Djihad Hadjadj and Harutyunyan, \{Ashot S.\} and Kumar, \{Kiran H.\} and Mirjam Blattner-Johnson and Jayne Vogelzang and Cecilia Sousa and Kang, \{Kyung Shin\} and Claire Sinai and Wang, \{Dayle K.\} and Prasidda Khadka and Kathleen Lewis and Lan Nguyen and Hayley Malkin and Patricia Ho and Ryan O{\textquoteright}Rourke and Shu Zhang and Rose Gold and Davy Deng and Jonathan Serrano and Matija Snuderl and Chris Jones and Wright, \{Karen D.\} and Chi, \{Susan N.\} and Jacques Grill and Kleinman, \{Claudia L.\} and Goumnerova, \{Liliana C.\} and Nada Jabado and Jones, \{David T.W.\} and Kieran, \{Mark W.\} and Ligon, \{Keith L.\} and Rameen Beroukhim and Pratiti Bandopadhayay",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = aug,

doi = "10.1038/s43018-022-00403-z",

language = "English",

volume = "3",

pages = "994--1011",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Research",

number = "8",

}

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 2022, 'Structural variants shape driver combinations and outcomes in pediatric high-grade glioma', Nature Cancer, vol. 3, no. 8, pp. 994-1011. https://doi.org/10.1038/s43018-022-00403-z

TY - JOUR

T1 - Structural variants shape driver combinations and outcomes in pediatric high-grade glioma

AU - Dubois, Frank P.B.

AU - Shapira, Ofer

AU - Greenwald, Noah F.

AU - Zack, Travis

AU - Wala, Jeremiah

AU - Tsai, Jessica W.

AU - Crane, Alexander

AU - Baguette, Audrey

AU - Hadjadj, Djihad

AU - Harutyunyan, Ashot S.

AU - Kumar, Kiran H.

AU - Blattner-Johnson, Mirjam

AU - Vogelzang, Jayne

AU - Sousa, Cecilia

AU - Kang, Kyung Shin

AU - Sinai, Claire

AU - Wang, Dayle K.

AU - Khadka, Prasidda

AU - Lewis, Kathleen

AU - Nguyen, Lan

AU - Malkin, Hayley

AU - Ho, Patricia

AU - O’Rourke, Ryan

AU - Zhang, Shu

AU - Gold, Rose

AU - Deng, Davy

AU - Serrano, Jonathan

AU - Snuderl, Matija

AU - Jones, Chris

AU - Wright, Karen D.

AU - Chi, Susan N.

AU - Grill, Jacques

AU - Kleinman, Claudia L.

AU - Goumnerova, Liliana C.

AU - Jabado, Nada

AU - Jones, David T.W.

AU - Kieran, Mark W.

AU - Ligon, Keith L.

AU - Beroukhim, Rameen

AU - Bandopadhayay, Pratiti

PY - 2022/8

Y1 - 2022/8

N2 - 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.

AB - 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.

KW - gliomas

UR - https://www.scopus.com/pages/publications/85133402053

U2 - 10.1038/s43018-022-00403-z

DO - 10.1038/s43018-022-00403-z

M3 - Article

C2 - 35788723

AN - SCOPUS:85133402053

SN - 2662-1347

VL - 3

SP - 994

EP - 1011

JO - Nature Cancer

JF - Nature Cancer

IS - 8

ER -

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

Abstract

UN SDGs

Keywords*

Field of Science*

Publication Type*

Access to Document

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