Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

Stacey Richardson; Rebecca M Hill; Christopher Kui; Janet C Lindsey; Yura Grabovksa; Claire Keeling; Louise Pease; Matthew Bashton; Stephen Crosier; Maria Vinci; Nicolas André; Dominique Figarella-Branger; Jordan R Hansford; Maria Lastowska; Krzysztof Zakrzewski; Mette Jorgensen; Jessica C Pickles; Michael D Taylor; Stefan M Pfister; Stephen B Wharton; Barry Pizer; Antony Michalski; Abhijit Joshi; Thomas S Jacques; Debbie Hicks; Edward C Schwalbe; Daniel Williamson; Vijay Ramaswamy; Simon Bailey; Steven C Clifford

doi:10.1093/neuonc/noab178

Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

Neuro Oncol. 2022 Jan 5;24(1):153-165. doi: 10.1093/neuonc/noab178.

Authors

Stacey Richardson¹, Rebecca M Hill¹, Christopher Kui¹, Janet C Lindsey¹, Yura Grabovksa¹, Claire Keeling¹, Louise Pease¹, Matthew Bashton^{1

2}, Stephen Crosier¹, Maria Vinci³, Nicolas André^{4

5}, Dominique Figarella-Branger^{6

7}, Jordan R Hansford⁷, Maria Lastowska⁸, Krzysztof Zakrzewski⁹, Mette Jorgensen¹⁰, Jessica C Pickles^{11

12}, Michael D Taylor¹³, Stefan M Pfister^{14

15

16}, Stephen B Wharton¹⁷, Barry Pizer¹⁸, Antony Michalski¹⁰, Abhijit Joshi¹⁹, Thomas S Jacques^{11

12}, Debbie Hicks¹, Edward C Schwalbe^{1

20}, Daniel Williamson¹, Vijay Ramaswamy¹³, Simon Bailey¹, Steven C Clifford¹

Affiliations

¹ Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University Centre for Cancer, Newcastle upon Tyne, UK.
² The Hub for Biotechnology in the Built Environment, Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK.
³ Department of Onco-Haematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy.
⁴ Department of Pediatric Hematology and Oncology, AP-HM, Marseille,France.
⁵ Institute of NeuroPhysiopathology, Aix-Marseille Universite, CNRS, Marseille, France.
⁶ CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, AP-HM, Marseille, France.
⁷ Children's Cancer Centre, Royal Children's Hospital, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁸ Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
⁹ Department of Neurosurgery, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
¹⁰ Department of Haematology and Oncology, Great Ormond Street Hospital for Children, London, UK.
¹¹ Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.
¹² Developmental Biology and Cancer Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
¹³ Programme in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁴ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
¹⁵ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁷ Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
¹⁸ Oncology Unit, Alder Hey Children's Hospital, Liverpool, UK.
¹⁹ Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
²⁰ Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK.

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.

Keywords: drivers; genomics; medulloblastoma; relapse; subgroups.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cerebellar Neoplasms* / genetics
DNA Copy Number Variations
Humans
Medulloblastoma* / genetics
Mutation
Neoplasm Recurrence, Local / genetics

Abstract

Publication types

MeSH terms

Grants and funding