| Autor: |
Frank Dubois, Ofer Shapira, Noah Greenwald, Travis Zack, Jeremiah Wala, Jessica Tsai, Djihad Hadjadj, Alexander Crane, Ashot Harutyunyan, Kiran Kumar, Mirjam Blattner-Johnson, Jayne Vogelzang, Cecila Sousa, Kyung Shin Kang, Claire Sinai, Dayle Wang, Prasidda Khadka, Kathleen Lewis, Lan Nguyen, Hayley Malkin, Patricia Ho, Ryan O’Rourke, Rose Gold, Davy Deng, Jonathan Serrano, Matija Snuderl, Karen Wright, Susan Chi, Jacques Grill, Claudia Kleiman, Liliana Goumnerova, Nada Jabado, David Jones, Mark Kieran, Keith Ligon, Rameen Beroukhim, Pratiti Bandopadhayay |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.21203/rs.3.rs-389596/v1 |
| Popis: |
Pediatric high-grade gliomas (pHGGs), encompassing hemispheric and diffuse midline gliomas (DMGs), remain a devastating disease. The last decade has revealed oncogenic drivers including single nucleotide variants (SNVs) in histones. However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored due to limitations in early SV analysis approaches. Using SV algorithms, we recently created, we analyzed SVs in whole-genome sequences of 179 pHGGs including a novel cohort of treatment naïve samples–the largest WGS cohort assembled in adult or pediatric glioma. The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases, including a novel SV amplifying a MYC enhancer in the lncRNA CCDC26 in 12% of DMGs and revealing a more central role for MYC in these cancers than previously known. Applying de novo SV signature discovery, we identified five signatures including three (SVsig1-3) involving primarily simple SVs, and two (SVsig4-5) involving complex, clustered SVs. These SV signatures associated with genetic variants that differed from what was observed for SV signatures in other cancers, suggesting different links to underlying biology. Tumors with simple SV signatures were TP53 wild-type but were enriched with 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 extrachromosomal amplicons that likely occurred later. 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 the complex SV signatures SVsig4-5 were associated with shorter overall survival independent of histone type and TP53 status. These data inform the role and impact of SVs in gliomagenesis and mechanisms that shape them. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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