Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas

Sibo Zhao ,Peter J Davies ,Yunfei Xia ,Tsz-Kwong Man ,D Williams Parsons ,Dalin Sun ,Holly Lindsay ,Huiyuan Zhang ,Sophie Xiao ,Yulun Huang ,Geoffrey Berguet ,Frank Braun ,Yuchen Du ,Yun Huang ,Adekunle M Adesina ,Murali Chintagumpala ,Xinyan Lu ,S Ding ,Anne-Clémence Veillard ,Jianfang Li ,László Perlaky ,Paola Genevini ,Lin Qi ,Wan-Yee Teo ,Jianhua Yang ,Sol Schvartzman ,Patrícia Baxter ,Lan Du ,Mari Kogiso ,Jack Su ,Jia Li ,Miklós Laczik ,Clifford Stephan ,Xiao-Nan Li

doi:10.1038/s41467-022-34514-z

Abstract

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.

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