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000276332 1001_ $$00000-0003-1153-6911$$aDonson, Andrew M$$b0
000276332 245__ $$aSignificant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: a multicenter study.
000276332 260__ $$aOxford$$bOxford Univ. Press$$c2023
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000276332 520__ $$aEpendymoma (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.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.DNA methylome derived copy number variants (CNVs) revealed large scale chromosome gains and losses at recurrence. 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 1 st recurrence. Multivariate survival analyses of this cohort showed that cases with 1q gain or 6q loss at 1 st 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.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.
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000276332 650_7 $$2Other$$achromosomal instability
000276332 650_7 $$2Other$$aependymoma
000276332 650_7 $$2Other$$aprognosis
000276332 650_7 $$2Other$$arecurrence
000276332 7001_ $$00000-0001-6382-5411$$aBertrand, Kelsey C$$b1
000276332 7001_ $$00000-0002-2464-7808$$aRiemondy, Kent A$$b2
000276332 7001_ $$00000-0003-3920-7060$$aGao, Dexiang$$b3
000276332 7001_ $$00000-0002-1822-2395$$aZhuang, Yonghua$$b4
000276332 7001_ $$00000-0002-2173-0198$$aSanford, Bridget$$b5
000276332 7001_ $$00000-0002-4131-5282$$aNorris, Gregory A$$b6
000276332 7001_ $$00000-0001-8050-8426$$aChapman, Rebecca J$$b7
000276332 7001_ $$aFu, Rui$$b8
000276332 7001_ $$00000-0003-4912-201X$$aWillard, Nicholas$$b9
000276332 7001_ $$00000-0002-2831-1009$$aGriesinger, Andrea M$$b10
000276332 7001_ $$00000-0003-1809-8539$$ade Sousa, Graziella Ribeiro$$b11
000276332 7001_ $$00000-0002-2280-2317$$aAmani, Vladimir$$b12
000276332 7001_ $$aGrimaldo, Enrique$$b13
000276332 7001_ $$00000-0002-6288-9496$$aHankinson, Todd C$$b14
000276332 7001_ $$aBooker, Ffyona$$b15
000276332 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b16$$udkfz
000276332 7001_ $$00000-0002-2585-2539$$aGrundy, Richard G$$b17
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000276332 7001_ $$aEllison, David W$$b19
000276332 7001_ $$00000-0003-4848-4801$$aForeman, Nicholas K$$b20
000276332 7001_ $$00000-0002-4438-6588$$aRitzmann, Timothy A$$b21
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