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| Página principal > Artículos > Artículos publicados > Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications |
(Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol) (Institut Germans Trias i Pujol) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Hospital del Mar d'Investigacions Mèdiques) (Institut d'Investigació Biomèdica de Bellvitge) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Hospital del Mar d'Investigacions Mèdiques) (Institut Germans Trias i Pujol) (Institut Germans Trias i Pujol)| Fecha: | 2020 |
| Resumen: | 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. |
| Ayudas: | Instituto de Salud Carlos III PI09-00751 Instituto de Salud Carlos III PI10-02082 Instituto de Salud Carlos III PI13-02340 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-490 Instituto de Salud Carlos III CB06-04-0033 European Commission 667273 Agència de Gestió d'Ajuts Universitaris i de Recerca 2019FIB01024 Instituto de Salud Carlos III CPII14-00021 Ministerio de Ciencia e Innovación RYC-2010-07249 Agència de Gestió d'Ajuts Universitaris i de Recerca SGR-1358 European Commission 826121 European Commission 668596 |
| Nota: | Altres ajuts: MSCBS/SAF2016-76390 |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | 14q32 ; BLCAP ; CHKA ; DLK1-DIO3 locus ; Hepatoblastoma (HB) ; Molecular risk stratification ; Prognostic biomarker ; RNA editing |
| Publicado en: | Journal of Hepatology, Vol. 73 Núm. 2 (august 2020) , p. 328-341, ISSN 1600-0641 |
