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Title: Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications
Author: Carrillo Reixach, Juan
Torrens, Laura
Simon Coma, Marina
Royo, Laura
Domingo Sàbat, Montserrat
Abril Fornaguera, Jordi
Akers, Nicholas
Sala, Margarita
Ragull, Sonia
Arnal, Magdalena
Villalmanzo, Núria
Cairo, Stefano
Villanueva Garatachea, Alberto
Kappler, Roland
Garrido, Marta
Guerra, Laura
Sabado, Constantino
Guillén, Gabriela
Mallo, Mar
Piñeyro, David
Vázquez Vitali, María
Kuchuk, Olga
Mateos, María Elena
Ramírez, Gema
López Santamaría, Manuel
Mozo, Yasmina
Soriano, Aroa
Grotzer, Michael
Branchereau, Sophie
García de Andoin, Nagore
López Ibor, Blanca
López Almaraz, Ricardo
Salinas, José Antonio
Torres, Bárbara
Hernández, Francisco
Uriz, José Javier
Fabre, Monique
Blanco, Julià
Paris, Claudia
Bajciová, Viera
Laureys, Geneviève
Masnou, Helena
Clos, Ariadna
Belendez, Cristina
Guettier, Catherine
Sumoy, Lauro
Planas, Ramón
Jordà, Mireia
Nonell, Lara
Czauderna, Piotr
Morland, Bruce
Sia, Daniela
Losic, Bojan
Buendia, Marie Annick
Sarrias, Maria Rosa
Llovet i Bayer, Josep Maria
Armengol, Carolina
Keywords: Càncer de fetge
Liver cancer
Issue Date: 1-Aug-2020
Publisher: Elsevier
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.
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It is part of: Journal of Hepatology, 2020, vol. 73, num. 2, p. 328-341
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Appears in Collections:Articles publicats en revistes (Medicina)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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