Journal Article

DKFZ-2021-01602

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse.

Richardson, S. ; Hill, R. M. ; Kui, C. ; Lindsey, J. C. ; Grabovksa, Y. ; Keeling, C. ; Pease, L. ; Bashton, M. ; Crosier, S. ; Vinci, M. ; André, N. ; Figarella-Branger, D. ; Hansford, J. R. ; Lastowska, M. ; Zakrzewski, K. ; Jorgensen, M. ; Pickles, J. C. ; Taylor, M. D. ; Pfister, S. M.DKFZ* ; Wharton, S. B. ; Pizer, B. ; Michalski, A. ; Joshi, A. ; Jacques, T. S. ; Hicks, D. ; Schwalbe, E. C. ; Williamson, D. ; Ramaswamy, V. ; Bailey, S. ; Clifford, S. C.

2022
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/neuonc/noab178

Abstract: <5% of medulloblastoma 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 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. MBSHH Non-infant displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (e.g. CDK amplifications) and novel (e.g. USH2A mutations) events. Importantly, many hallmark features of medulloblastoma were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (e.g. 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 (e.g. DNA damage-signaling) and specific events (e.g. 3p loss) predicted survival post-relapse.rMB is defined 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.

Keyword(s): Drivers ; Genomics ; Medulloblastoma ; Relapse ; Subgroups

Note: 2022 Jan 5;24(1):153-165

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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