Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas

Sibo Zhao, Jia Li, Huiyuan Zhang, Lin Qi, Yuchen Du, Mari Kogiso, Frank K. Braun, Sophie Xiao, Yulun Huang, Jianfang Li, Wan-Yee Teo, Holly Lindsay, Patricia Baxter, Jack M. F. Su, Adekunle Adesina, Miklós Laczik, Paola Genevini, Anne-Clemence Veillard, Sol Schvartzman, Geoffrey Berguet, Shi-Rong Ding, Liping Du, Clifford Stephan, Jianhua Yang, Peter J. A. Davies, Xinyan Lu, Murali Chintagumpala, Donald William Parsons, Laszlo Perlaky, Yun-Fei Xia, Tsz-Kwong Man, Yun Huang, Deqiang Sun () and Xiao-Nan Li ()
Additional contact information
Sibo Zhao: Texas Children’s Hospital, Baylor College of Medicine
Jia Li: Texas A&M University
Huiyuan Zhang: Texas Children’s Hospital, Baylor College of Medicine
Lin Qi: Texas Children’s Hospital, Baylor College of Medicine
Yuchen Du: Texas Children’s Hospital, Baylor College of Medicine
Mari Kogiso: Texas Children’s Hospital, Baylor College of Medicine
Frank K. Braun: Texas Children’s Hospital, Baylor College of Medicine
Sophie Xiao: Northwestern University Feinberg School of Medicine
Yulun Huang: Texas Children’s Hospital, Baylor College of Medicine
Jianfang Li: Texas A&M University
Wan-Yee Teo: National Cancer Center Singapore
Holly Lindsay: Texas Children’s Hospital, Baylor College of Medicine
Patricia Baxter: Texas Children’s Hospital, Baylor College of Medicine
Jack M. F. Su: Texas Children’s Hospital, Baylor College of Medicine
Adekunle Adesina: Baylor College of Medicine
Miklós Laczik: Epigenetic Services
Paola Genevini: Epigenetic Services
Anne-Clemence Veillard: Epigenetic Services
Sol Schvartzman: Epigenetic Services
Geoffrey Berguet: Epigenetic Services
Shi-Rong Ding: Sun Yat-sen University Cancer Center
Liping Du: Northwestern University Feinberg School of Medicine
Clifford Stephan: Texas A&M University
Jianhua Yang: Texas Children’s Hospital, Baylor College of Medicine
Peter J. A. Davies: Texas A&M University
Xinyan Lu: Northwestern University Feinberg School of Medicine
Murali Chintagumpala: Texas Children’s Hospital, Baylor College of Medicine
Donald William Parsons: Texas Children’s Hospital, Baylor College of Medicine
Laszlo Perlaky: Texas Children’s Hospital, Baylor College of Medicine
Yun-Fei Xia: Sun Yat-sen University Cancer Center
Tsz-Kwong Man: Texas Children’s Hospital, Baylor College of Medicine
Yun Huang: Texas A&M University
Deqiang Sun: Texas A&M University
Xiao-Nan Li: Texas Children’s Hospital, Baylor College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34514-z

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