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

Applied Sciences Department

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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 MB _SHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MB _Group4 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
Article number	noab178
Pages (from-to)	153-165
Number of pages	13
Journal	Neuro-Oncology
Volume	24
Issue number	1
Early online date	17 Jul 2021
DOIs	https://doi.org/10.1093/neuonc/noab178
Publication status	Published - 1 Jan 2022

Keywords

Drivers
Genomics
Medulloblastoma
Relapse
Subgroups

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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. Article noab178. https://doi.org/10.1093/neuonc/noab178

@article{0cd6270a89ba4b8eb84b21cbe80f3d4d,

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 MB SHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MB Group4 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",

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 = "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{\textquoteright}s Charity), Children{\textquoteright}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{\textquoteright}s Lemonade Stand Young Investigator Award.",

year = "2022",

month = jan,

day = "1",

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, noab178, 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.

N1 - 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.

PY - 2022/1/1

Y1 - 2022/1/1

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 MB SHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MB Group4 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 MB SHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MB Group4 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 - Drivers

KW - Genomics

KW - Medulloblastoma

KW - Relapse

KW - Subgroups

UR - http://www.scopus.com/inward/record.url?scp=85121728083&partnerID=8YFLogxK

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

M1 - noab178

ER -

Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

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