RT Journal Article
T1 Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications.
A1 Carrillo-Reixach, Juan
A1 Torrens, Laura
A1 Simon-Coma, Marina
A1 Royo, Laura
A1 Domingo-Sàbat, Montserrat
A1 Abril-Fornaguera, Jordi
A1 Akers, Nicholas
A1 Sala, Margarita
A1 Ragull, Sonia
A1 Arnal, Magdalena
A1 Villalmanzo, Núria
A1 Cairo, Stefano
A1 Villanueva, Alberto
A1 Kappler, Roland
A1 Garrido, Marta
A1 Guerra, Laura
A1 Sábado, Constantino
A1 Guillén, Gabriela
A1 Mallo, Mar
A1 Piñeyro, David
A1 Vázquez-Vitali, María
A1 Kuchuk, Olga
A1 Mateos, María Elena
A1 Ramírez, Gema
A1 Santamaría, Manuel López
A1 Mozo, Yasmina
A1 Soriano, Aroa
A1 Grotzer, Michael
A1 Branchereau, Sophie
A1 de Andoin, Nagore García
A1 López-Ibor, Blanca
A1 López-Almaraz, Ricardo
A1 Salinas, José Antonio
A1 Torres, Bárbara
A1 Hernández, Francisco
A1 Uriz, José Javier
A1 Fabre, Monique
A1 Blanco, Julià
A1 Paris, Claudia
A1 Bajčiová, Viera
A1 Laureys, Geneviève
A1 Masnou, Helena
A1 Clos, Ariadna
A1 Belendez, Cristina
A1 Guettier, Catherine
A1 Sumoy, Lauro
A1 Planas, Ramón
A1 Jordà, Mireia
A1 Nonell, Lara
A1 Czauderna, Piotr
A1 Morland, Bruce
A1 Sia, Daniela
A1 Losic, Bojan
A1 Buendia, Marie Annick
A1 Sarrias, Maria Rosa
A1 Llovet, Josep M
A1 Armengol, Carolina
K1 14q32
K1 BLCAP
K1 CHKA
K1 DLK1-DIO3 locus
K1 Hepatoblastoma (HB)
K1 Molecular risk stratification
K1 Prognostic biomarker
K1 RNA editing
AB 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. We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. 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. 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. 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.
YR 2020
FD 2020-03-30
LK http://hdl.handle.net/10668/15313
UL http://hdl.handle.net/10668/15313
LA en
DS RISalud
RD Apr 12, 2025