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

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 WhartonBarry Pizer, Antony Michalski, Abhijit Joshi, Thomas S Jacques, Debbie Hicks, Edward C Schwalbe, Daniel Williamson, Vijay Ramaswamy, Simon Bailey, Steven C Clifford

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

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.

Original language	English
Pages (from-to)	153-165
Number of pages	13
Journal	Neuro-oncology
Volume	24
Issue number	1
DOIs	https://doi.org/10.1093/neuonc/noab178
Publication status	Published or Issued - 5 Jan 2022
Externally published	Yes

Keywords

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

Access to Document

10.1093/neuonc/noab178

Cite this

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., ... Clifford, S. C. (2022). Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse. Neuro-oncology, 24(1), 153-165. https://doi.org/10.1093/neuonc/noab178

@article{19ef17b5d04a4942a9c2c0c1e0e8d0b5,

title = "Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse",

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

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

note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.",

year = "2022",

month = jan,

day = "5",

doi = "10.1093/neuonc/noab178",

language = "English",

volume = "24",

pages = "153--165",

journal = "Neuro-oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "1",

}

Richardson, S, Hill, RM, Kui, C, Lindsey, JC, Grabovksa, Y, Keeling, C, Pease, L, Bashton, M, Crosier, S, Vinci, M, André, N, Figarella-Branger, D, Hansford, JR, Lastowska, M, Zakrzewski, K, Jorgensen, M, Pickles, JC, Taylor, MD, Pfister, SM, Wharton, SB, Pizer, B, Michalski, A, Joshi, A, Jacques, TS, Hicks, D, Schwalbe, EC, Williamson, D, Ramaswamy, V, Bailey, S & Clifford, SC 2022, 'Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse', Neuro-oncology, vol. 24, no. 1, pp. 153-165. https://doi.org/10.1093/neuonc/noab178

TY - JOUR

T1 - Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

AU - Richardson, Stacey

AU - Hill, Rebecca M

AU - Kui, Christopher

AU - Lindsey, Janet C

AU - Grabovksa, Yura

AU - Keeling, Claire

AU - Pease, Louise

AU - Bashton, Matthew

AU - Crosier, Stephen

AU - Vinci, Maria

AU - André, Nicolas

AU - Figarella-Branger, Dominique

AU - Hansford, Jordan R

AU - Lastowska, Maria

AU - Zakrzewski, Krzysztof

AU - Jorgensen, Mette

AU - Pickles, Jessica C

AU - Taylor, Michael D

AU - Pfister, Stefan M

AU - Wharton, Stephen B

AU - Pizer, Barry

AU - Michalski, Antony

AU - Joshi, Abhijit

AU - Jacques, Thomas S

AU - Hicks, Debbie

AU - Schwalbe, Edward C

AU - Williamson, Daniel

AU - Ramaswamy, Vijay

AU - Bailey, Simon

AU - Clifford, Steven C

PY - 2022/1/5

Y1 - 2022/1/5

N2 - 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.

AB - 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.

KW - Cerebellar Neoplasms/genetics

KW - DNA Copy Number Variations

KW - Humans

KW - Medulloblastoma/genetics

KW - Mutation

KW - Neoplasm Recurrence, Local/genetics

U2 - 10.1093/neuonc/noab178

DO - 10.1093/neuonc/noab178

M3 - Article

C2 - 34272868

SN - 1522-8517

VL - 24

SP - 153

EP - 165

JO - Neuro-oncology

JF - Neuro-oncology

IS - 1

ER -