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

Frank P B DubiosOfer ShapiraNoah F GreenwaldTravis ZackJeremiah WalaJessica W TsaiAlexander CraneAudrey BaguetteDjihad HadjadjAshot S HarutyunyanKiran H KumarMirjam Blattner-JohnsonJayne VogelzangCecilia SousaKyung Shin KangClaire SinaiDayle K WangPrasidda KhadkaKathleen LewisLan NguyenHayley MalkinPatricia HoRyan O'RourkeShu ZhangRose GoldDavy DengJonathan SerranoMatija SnuderlChris JonesKaren D WrightSusan N ChiJacques GrillClaudia L KleinmanLiliana Christova GoumnerovaNada JabadoDavid T W JonesMark W KieranKeith L LigonRameen BeroukhimPratiti Bandopadhayay
Published in: Nature cancer (2022)
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.
Keyphrases
  • high grade
  • low grade
  • genome wide
  • copy number
  • transcription factor
  • wild type
  • dna methylation
  • gene expression
  • single cell
  • cancer therapy
  • metabolic syndrome
  • big data