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Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications

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dc.contributor.author Carrillo-Reixach, Juan
dc.contributor.author Arnal, Magdalena
dc.contributor.author Nonell Mazelón, Lara
dc.contributor.author Armengol, Carolina
dc.date.accessioned 2021-05-07T07:07:56Z
dc.date.available 2021-05-07T07:07:56Z
dc.date.issued 2020
dc.identifier.citation Carrillo-Reixach J, Torrens L, Simon-Coma M, Royo L, Domingo-Sàbat M, Abril-Fornaguera J, et al. Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications. J Hepatol. 2020 Aug; 73(2): 328-41. DOI: 10.1016/j.jhep.2020.03.025
dc.identifier.issn 0168-8278
dc.identifier.uri http://hdl.handle.net/10230/47350
dc.description.abstract Background & aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. Methods: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. Results: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. Conclusions: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. Lay summary: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.rights © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). J. Hepatol. 2020, 73, 328–341.
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.title Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.jhep.2020.03.025
dc.subject.keyword 14q32
dc.subject.keyword BLCAP
dc.subject.keyword CHKA
dc.subject.keyword DLK1-DIO3 locus
dc.subject.keyword Hepatoblastoma (HB)
dc.subject.keyword Molecular risk stratification
dc.subject.keyword Prognostic biomarker
dc.subject.keyword RNA editing
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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