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Article Dans Une Revue Neuro-Oncology Année : 2022

Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

Stacey Richardson
  • Fonction : Auteur
Rebecca Hill
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Christopher Kui
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Janet Lindsey
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Yura Grabovksa
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Claire Keeling
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Louise Pease
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Matthew Bashton
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Stephen Crosier
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Maria Vinci
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Nicolas André
Dominique Figarella‑branger
Jordan Hansford
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Maria Lastowska
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Krzysztof Zakrzewski
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Mette Jorgensen
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Jessica Pickles
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Michael Taylor
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Stefan Pfister
Stephen Wharton
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Barry Pizer
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Antony Michalski
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Abhijit Joshi
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Thomas Jacques
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Debbie Hicks
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Edward Schwalbe
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Daniel Williamson
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Vijay Ramaswamy
Simon Bailey
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Steven Clifford
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Résumé

Abstract Background Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease. Methods We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54). Results Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (eg, CDK amplifications) and novel (eg, USH2A mutations) events. Importantly, many hallmark features of MB were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (eg, SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (eg, DNA damage signaling) and specific events (eg, 3p loss) predicted survival post-relapse. Conclusions rMB is characterised by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.
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Dates et versions

hal-03603918 , version 1 (10-03-2022)

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Stacey Richardson, Rebecca Hill, Christopher Kui, Janet Lindsey, Yura Grabovksa, et al.. Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse. Neuro-Oncology, 2022, 24 (1), pp.153-165. ⟨10.1093/neuonc/noab178⟩. ⟨hal-03603918⟩
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