Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

Richardson, Stacey, Hill, Rebecca M., Kui, Christopher, Lindsey, Janet C., Grabovksa, Yura, Keeling, Claire, Pease, Louise, Bashton, Matthew, Crosier, Stephen, Vinci, Maria, André, Nicolas, Figarella-Branger, Dominique, Hansford, Jordan R., Lastowska, Maria, Zakrzewski, Krzysztof, Jorgensen, Mette, Pickles, Jessica C., Taylor, Michael D., Pfister, Stefan M., Wharton, Stephen B., Pizer, Barry, Michalski, Antony, Joshi, Abhijit, Jacques, Thomas S., Hicks, Debbie, Schwalbe, Edward, Williamson, Daniel, Ramaswamy, Vijay, Bailey, Simon and Clifford, Steven C. (2022) Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse. Neuro-Oncology, 24 (1). pp. 153-165. ISSN 1522-8517

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Official URL: https://doi.org/10.1093/neuonc/noab178


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.

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).

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.

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.

Item Type: Article
Additional Information: Funding information: This study was funded by Cancer Research UK, the INSTINCT network (co-funded by The Brain Tumour Charity, Children with Cancer UK, and Great Ormond Street Hospital Children’s Charity), Children’s Cancer North, Action Medical Research, The Tom Grahame Trust, JGW Patterson Foundation, Star for Harris, the C.R. Younger Foundation, and the Canadian Institutes for Health Research. V.R. is in receipt of an Alex’s Lemonade Stand Young Investigator Award.
Uncontrolled Keywords: Drivers, genomics, medulloblastoma, relaps, subgroups
Subjects: A300 Clinical Medicine
C100 Biology
C400 Genetics
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: John Coen
Date Deposited: 27 Jul 2021 10:08
Last Modified: 02 Sep 2022 10:45
URI: https://nrl.northumbria.ac.uk/id/eprint/46763

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