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; Xiaonan Li

doi:10.1038/s41467-022-34514-z

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 BerguetShi 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, Xiaonan Li^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Article number	6689
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34514-z
State	Published - Dec 2022

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Zhao, S., Li, J., Zhang, H., Qi, L., Du, Y., Kogiso, M., Braun, F. K., Xiao, S., Huang, Y., Li, J., Teo, W. Y., Lindsay, H., Baxter, P., Su, J. M. F., Adesina, A., Laczik, M., Genevini, P., Veillard, A. C., Schvartzman, S., ... Li, X. (2022). Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas. Nature communications, 13(1), Article 6689. https://doi.org/10.1038/s41467-022-34514-z

@article{651d49fc88454c0fa77e945d37a0c30f,

title = "Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas",

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.",

author = "Sibo Zhao and Jia Li and Huiyuan Zhang and Lin Qi and Yuchen Du and Mari Kogiso and Braun, {Frank K.} and Sophie Xiao and Yulun Huang and Jianfang Li and Teo, {Wan Yee} and Holly Lindsay and Patricia Baxter and Su, {Jack M.F.} and Adekunle Adesina and Mikl{\'o}s Laczik and Paola Genevini and Veillard, {Anne Clemence} and Sol Schvartzman and Geoffrey Berguet and Ding, {Shi Rong} and Liping Du and Clifford Stephan and Jianhua Yang and Davies, {Peter J.A.} and Xinyan Lu and Murali Chintagumpala and Parsons, {Donald William} and Laszlo Perlaky and Xia, {Yun Fei} and Man, {Tsz Kwong} and Yun Huang and Deqiang Sun and Xiaonan Li",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-34514-z",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

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Zhao, S, Li, J, Zhang, H, Qi, L, Du, Y, Kogiso, M, Braun, FK, Xiao, S, Huang, Y, Li, J, Teo, WY, Lindsay, H, Baxter, P, Su, JMF, Adesina, A, Laczik, M, Genevini, P, Veillard, AC, Schvartzman, S, Berguet, G, Ding, SR, Du, L, Stephan, C, Yang, J, Davies, PJA, Lu, X, Chintagumpala, M, Parsons, DW, Perlaky, L, Xia, YF, Man, TK, Huang, Y, Sun, D & Li, X 2022, 'Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas', Nature communications, vol. 13, no. 1, 6689. https://doi.org/10.1038/s41467-022-34514-z

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T1 - Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas

AU - Zhao, Sibo

AU - Li, Jia

AU - Zhang, Huiyuan

AU - Qi, Lin

AU - Du, Yuchen

AU - Kogiso, Mari

AU - Braun, Frank K.

AU - Xiao, Sophie

AU - Huang, Yulun

AU - Li, Jianfang

AU - Teo, Wan Yee

AU - Lindsay, Holly

AU - Baxter, Patricia

AU - Su, Jack M.F.

AU - Adesina, Adekunle

AU - Laczik, Miklós

AU - Genevini, Paola

AU - Veillard, Anne Clemence

AU - Schvartzman, Sol

AU - Berguet, Geoffrey

AU - Ding, Shi Rong

AU - Du, Liping

AU - Stephan, Clifford

AU - Yang, Jianhua

AU - Davies, Peter J.A.

AU - Lu, Xinyan

AU - Chintagumpala, Murali

AU - Parsons, Donald William

AU - Perlaky, Laszlo

AU - Xia, Yun Fei

AU - Man, Tsz Kwong

AU - Huang, Yun

AU - Sun, Deqiang

AU - Li, Xiaonan

PY - 2022/12

Y1 - 2022/12

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AB - 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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Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas

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