Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study

Edward Schwalbe; Janet C. Lindsey; Marina Danilenko; Rebecca M. Hill; Stephen Crosier; Sarra L. Ryan; Daniel Williamson; Jemma Castle; Debbie Hicks; Marcel Kool; Till Milde; Andrey Korshunov; Stefan M. Pfister; Simon Bailey; Steven C. Clifford

doi:10.1093/neuonc/noae178

Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study

Edward Schwalbe, Janet C. Lindsey, Marina Danilenko, Rebecca M. Hill, Stephen Crosier, Sarra L. Ryan, Daniel Williamson, Jemma Castle, Debbie Hicks, Marcel Kool, Till Milde, Andrey Korshunov, Stefan M. Pfister, Simon Bailey, Steven C. Clifford^*

^*Corresponding author for this work

Applied Sciences Department

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

2 Citations (Scopus)

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Abstract

Background

MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients’ MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management.

Methods

We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases.

Results

Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a “canonical” very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS.

Conclusions

MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR “canonical” MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.

Original language	English
Article number	noae178
Pages (from-to)	222–236
Number of pages	15
Journal	Neuro-Oncology
Volume	27
Issue number	1
Early online date	8 Oct 2024
DOIs	https://doi.org/10.1093/neuonc/noae178
Publication status	Published - 12 Jan 2025

Keywords

MYC amplification
MYCN amplification
medulloblastoma
survival

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Schwalbe, E., Lindsey, J. C., Danilenko, M., Hill, R. M., Crosier, S., Ryan, S. L., Williamson, D., Castle, J., Hicks, D., Kool, M., Milde, T., Korshunov, A., Pfister, S. M., Bailey, S., & Clifford, S. C. (2025). Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study. Neuro-Oncology, 27(1), 222–236. Article noae178. https://doi.org/10.1093/neuonc/noae178

@article{5e8c60eb55e04d0c898362eb3649b02f,

title = "Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study",

abstract = "BackgroundMYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients{\textquoteright} MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management.MethodsWe characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases.ResultsMost MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a “canonical” very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS.ConclusionsMYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR “canonical” MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.",

keywords = "MYC amplification, MYCN amplification, medulloblastoma, survival",

author = "Edward Schwalbe and Lindsey, {Janet C.} and Marina Danilenko and Hill, {Rebecca M.} and Stephen Crosier and Ryan, {Sarra L.} and Daniel Williamson and Jemma Castle and Debbie Hicks and Marcel Kool and Till Milde and Andrey Korshunov and Pfister, {Stefan M.} and Simon Bailey and Clifford, {Steven C.}",

year = "2025",

month = jan,

day = "12",

doi = "10.1093/neuonc/noae178",

language = "English",

volume = "27",

pages = "222–236",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "1",

}

Schwalbe, E, Lindsey, JC, Danilenko, M, Hill, RM, Crosier, S, Ryan, SL, Williamson, D, Castle, J, Hicks, D, Kool, M, Milde, T, Korshunov, A, Pfister, SM, Bailey, S & Clifford, SC 2025, 'Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study', Neuro-Oncology, vol. 27, no. 1, noae178, pp. 222–236. https://doi.org/10.1093/neuonc/noae178

TY - JOUR

T1 - Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes

T2 - A multicenter cohort study

AU - Schwalbe, Edward

AU - Lindsey, Janet C.

AU - Danilenko, Marina

AU - Hill, Rebecca M.

AU - Crosier, Stephen

AU - Ryan, Sarra L.

AU - Williamson, Daniel

AU - Castle, Jemma

AU - Hicks, Debbie

AU - Kool, Marcel

AU - Milde, Till

AU - Korshunov, Andrey

AU - Pfister, Stefan M.

AU - Bailey, Simon

AU - Clifford, Steven C.

PY - 2025/1/12

Y1 - 2025/1/12

N2 - BackgroundMYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients’ MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management.MethodsWe characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases.ResultsMost MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a “canonical” very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS.ConclusionsMYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR “canonical” MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.

AB - BackgroundMYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients’ MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management.MethodsWe characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases.ResultsMost MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a “canonical” very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS.ConclusionsMYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR “canonical” MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.

KW - MYC amplification

KW - MYCN amplification

KW - medulloblastoma

KW - survival

UR - http://www.scopus.com/inward/record.url?scp=85212116993&partnerID=8YFLogxK

U2 - 10.1093/neuonc/noae178

DO - 10.1093/neuonc/noae178

M3 - Article

SN - 1522-8517

VL - 27

SP - 222

EP - 236

JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 1

M1 - noae178

ER -

Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study

Abstract

Keywords

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