Journal
NATURE CANCER
Volume 3, Issue 8, Pages 994-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s43018-022-00403-z
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Funding
- National Institutes of Health (NIH) [NIH R37 5R37CA255245-02, NIH R01 CA188228, R01 CA215489, R01 CA219943]
- German Research Foundation
- Fund for Innovative Cancer Informatics
- Gray Matters Brain Cancer Foundation
- Bridge Project of MIT and Dana-Farber/Harvard Cancer Center
- Sontag Foundation
- V Foundation for Cancer Research
- Michael Mosier Defeat DIPG Foundation
- ChadTough Foundation
- St. Baldrick's Foundation
- Maria Foundation
- Pediatric Brain Tumor Foundation
- Friends of DFCI
- Alex's Lemonade Stand Foundation
- Broad Institute Escape Velocity Award
- Imagine for Margo and Lemos Family
- Frederic Lemos and the Gustave Roussy Foundation
- Pussycat Foundation Helen Gurley Brown Presidential Initiative
- Canadian Institutes of Health Research
- Genome Canada
- Zach Carson Fund
- Ellie Kavalieros DIPG Fund
- Ryan Harvey Fund
- Mikey Czech DIPG Foundation
- Caroline Cronk Fund
- Markoff Art in Giving Foundation
- Brock Fleming Fund
- Stop and Shop Pediatric Brain Tumor Program
- Cure Starts Now
- Mayo Clinic Comprehensive Cancer Center Grant - National Cancer Institute [P30CA15083]
- DIPG Collaborative
- Giving for Gabi Fund
- Jared Branfman Sunflowers for Life Fund
- McKennaClaire Foundation
- We Love You Connie Foundation
- Compute Canada
- Calcul Quebec
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This study analyzed the contributions of structural variants (SVs) to the development of pediatric high-grade gliomas (pHGGs). The researchers found that the most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases (RTKs), indicating an underappreciated role for MYC in pHGG. The study also identified different patterns of simple and complex SVs, with complex SVs associated with shorter overall survival in certain types of pHGGs. These findings provide important insights into the impact of SVs on gliomagenesis and tumor evolution.
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. Dubois and colleagues assemble a large cohort of human pediatric high-grade glioma samples, identifying patterns of simple and complex structural variants and characterizing their role in tumor development and evolution.
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