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

Nat Cancer. 2022 Aug;3(8):994-1011. doi: 10.1038/s43018-022-00403-z. Epub 2022 Jul 4.

Authors

Frank P B Dubois^{1

2}, Ofer Shapira^{1

2}, Noah F Greenwald^{1

2}, Travis Zack^{1

2}, Jeremiah Wala^{1

2}, Jessica W Tsai^{2

3

4}, Alexander Crane^{1

2}, Audrey Baguette⁵, Djihad Hadjadj⁶, Ashot S Harutyunyan⁶, Kiran H Kumar^{1

2}, Mirjam Blattner-Johnson^{7

8}, Jayne Vogelzang⁹, Cecilia Sousa⁹, Kyung Shin Kang^{1

2}, Claire Sinai⁹, Dayle K Wang^{2

4}, Prasidda Khadka^{1

2}, Kathleen Lewis², Lan Nguyen², Hayley Malkin⁹, Patricia Ho^{1

2}, Ryan O'Rourke^{1

2}, Shu Zhang^{1

2}, Rose Gold^{1

2}, Davy Deng^{1

2}, Jonathan Serrano¹⁰, Matija Snuderl¹⁰, Chris Jones¹¹, Karen D Wright^{3

4}, Susan N Chi^{3

4}, Jacques Grill¹², Claudia L Kleinman^{6

13}, Liliana C Goumnerova^{14

15}, Nada Jabado^{6

16}, David T W Jones^{7

8}, Mark W Kieran^{2

3

4

15}, Keith L Ligon^{17

18

19

20}, Rameen Beroukhim^{21

22

23}, Pratiti Bandopadhayay^{24

25

26}

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁴ Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
⁵ Quantitative Life Sciences, McGill University, Montreal, QC, Canada.
⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada.
⁷ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁸ Division of Pediatric Glioma Research, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹⁰ New York University Medical Center, New York, NY, USA.
¹¹ Division of Cancer Therapeutics and Department of Molecular Pathology, Institute of Cancer Research 15 Cotswold Road, Sutton, London, UK.
¹² Department of Pediatric and Adolescent Oncology and INSERM Unit 981, Gustave Roussy Institute and University of Paris Saclay, Villejuif, France.
¹³ Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada.
¹⁴ Department of Neurosurgery, Boston Children's Hospital; Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
¹⁵ LCG: Tromboprotea, MWK: Day One Biopharmaceuticals, San Francisco, CA, USA.
¹⁶ Division of Experimental Medicine, Department of Medicine and Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
¹⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA. keith_ligon@dfci.harvard.edu.
¹⁸ Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. keith_ligon@dfci.harvard.edu.
¹⁹ Department of Pathology, Brigham & Women's Hospital and Boston Children's Hospital, Boston, USA. keith_ligon@dfci.harvard.edu.
²⁰ Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA. keith_ligon@dfci.harvard.edu.
²¹ Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. rameen_beroukhim@dfci.harvard.edu.
²² Broad Institute of MIT and Harvard, Cambridge, MA, USA. rameen_beroukhim@dfci.harvard.edu.
²³ Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. rameen_beroukhim@dfci.harvard.edu.
²⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. pratiti_bandopadhayay@dfci.harvard.edu.
²⁵ Department of Pediatrics, Harvard Medical School, Boston, MA, USA. pratiti_bandopadhayay@dfci.harvard.edu.
²⁶ Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA. pratiti_bandopadhayay@dfci.harvard.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Brain Neoplasms* / genetics
Cell Cycle Proteins / genetics
Child
Glioma* / genetics
Histones / genetics
Humans
Mutation
Proto-Oncogene Proteins / genetics

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding