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Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas
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Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas
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Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas
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Journal Article
Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas
2022
Overview
Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs (
CACNA1H, SLC12A7, RARA
in RELA and
HSPB8, GMPR, ITGB4
in PFA) and potential booster DMRs (
PLEKHG1
in RELA and
NOTCH, EPHA2, SUFU, FOXJ1
in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies.
While recurrence is frequent in ependymoma, the underlying molecular mechanisms remain to be explored. Here, the authors investigate epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses over 13 years and identify distinct patterns of DNA methylation.
