Skip to main content

Research Repository

Advanced Search

Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: a multicenter study

Donson, Andrew M; Bertrand, Kelsey C; Riemondy, Kent A; Gao, Dexiang; Zhuang, Yonghua; Sanford, Bridget; Norris, Gregory A; Chapman, Rebecca J; Fu, Rui; Willard, Nicholas; Griesinger, Andrea M; de Sousa, Graziella Ribeiro; Amani, Vladimir; Grimaldo, Enrique; Hankinson, Todd C; Booker, Ffyona; Sill, Martin; Grundy, Richard G; Pajtler, Kristian W; Ellison, David W; Foreman, Nicholas K; Ritzmann, Timothy A

Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: a multicenter study Thumbnail


Authors

Andrew M Donson

Kelsey C Bertrand

Kent A Riemondy

Dexiang Gao

Yonghua Zhuang

Bridget Sanford

Gregory A Norris

Rebecca J Chapman

Rui Fu

Nicholas Willard

Andrea M Griesinger

Graziella Ribeiro de Sousa

Vladimir Amani

Enrique Grimaldo

Todd C Hankinson

Ffyona Booker

Martin Sill

Kristian W Pajtler

David W Ellison

Nicholas K Foreman



Abstract

Background
Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN molecular groups. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA remains largely unknown; however, the increasing use of surgery at first recurrence has now provided access to clinical samples to facilitate a better understanding of this.

Methods
In this large longitudinal international multicenter study, we examined matched samples of primary and recurrent disease from PFA patients to investigate the biology of recurrence.

Results
DNA methylome derived copy number variants (CNVs) revealed large-scale chromosome gains and losses at recurrence in PFA. CNV changes were dominated by chromosome 1q gain and/or 6q loss, both previously identified as high-risk factors in PFA, which were present in 23% at presentation but increased to 61% at first recurrence. Multivariate survival analyses of this cohort showed that cases with 1q gain or 6q loss at first recurrence were significantly more likely to recur again. Predisposition to 1q+/6q− CNV changes at recurrence correlated with hypomethylation of heterochromatin-associated DNA at presentation. Cellular and molecular analyses revealed that 1q+/6q− PFA had significantly higher proportions of proliferative neuroepithelial undifferentiated progenitors and decreased differentiated neoplastic subpopulations.

Conclusions
This study provides clinically and preclinically actionable insights into the biology of PFA recurrence. The hypomethylation predisposition signature in PFA is a potential risk-classifier for trial stratification. We show that the cellular heterogeneity of PFAs evolves largely because of genetic evolution of neoplastic cells.

Citation

Donson, A. M., Bertrand, K. C., Riemondy, K. A., Gao, D., Zhuang, Y., Sanford, B., Norris, G. A., Chapman, R. J., Fu, R., Willard, N., Griesinger, A. M., de Sousa, G. R., Amani, V., Grimaldo, E., Hankinson, T. C., Booker, F., Sill, M., Grundy, R. G., Pajtler, K. W., Ellison, D. W., …Ritzmann, T. A. (2023). Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: a multicenter study. Neuro-Oncology, 25(10), 1854-1867. https://doi.org/10.1093/neuonc/noad096

Journal Article Type Article
Acceptance Date May 29, 2023
Online Publication Date May 29, 2023
Publication Date 2023-10
Deposit Date Feb 5, 2025
Publicly Available Date Feb 27, 2025
Journal Neuro-Oncology
Print ISSN 1522-8517
Electronic ISSN 1523-5866
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 25
Issue 10
Pages 1854-1867
DOI https://doi.org/10.1093/neuonc/noad096
Keywords Cancer Research; Neurology (clinical); Oncology
Public URL https://nottingham-repository.worktribe.com/output/21378425
Publisher URL https://academic.oup.com/neuro-oncology/article/25/10/1854/7184179
Related Public URLs https://pmc.ncbi.nlm.nih.gov/articles/pmid/37246777/

Files





You might also like



Downloadable Citations