Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications

• DOI: 10.1016/j.jhep.2020.03.025
• Publication Date: 2020-03-30T14:53:28Z
• Authors: Juan Carrillo-Rei...; Laura Torrens; Marina Simon-Coma; Laura Royo; Montserrat Doming...; Jordi Abril-Forna...; Nicholas Akers; Margarita Sala; Sonia Ragull; Magdalena Arnal; Núria Villalmanzo; Stefano Cairo; Alberto Villanueva; Roland Kappler; Marta Garrido; Laura Guerra; Constantino Sábado; Gabriela Guillén; Mar Mallo; David Piñeyro; María Vázquez-Vitali; Olga Kuchuk; María Elena Mateos; Gema Ramírez; Manuel López Sant...; Yasmina Mozo; Aroa Soriano; Michael Grotzer; Sophie Branchereau; Nagore García de ...; Blanca López-Ibor; Ricardo López-Alm...; José Antonio Salinas; Bárbara Torres; Francisco Hernández; José Javier Uriz; Monique Fabre; Julià Blanco; Claudia Paris; Viera Bajčiová; Geneviève Laureys; Helena Masnou; Ariadna Clos; Cristina Belendez; Catherine Guettier; Lauro Sumoy; Ramón Planas; Mireia Jordà; Lara Nonell; Piotr Czauderna; Bruce Morland; Daniela Sia; Bojan Losic; Marie Annick Buendia; Maria Rosa Sarrias; Josep M. Llovet; Carolina Armengol
• Keywords: Epigenomics; Hepatoblastoma; CpG site

Hepatoblastoma (HB) is a rare disease. Nevertheless, it the predominant pediatric liver cancer, with limited therapeutic options for patients aggressive tumors. Herein, we aimed to uncover mechanisms of HB pathobiology and identify new biomarkers targets in move towards precision medicine advanced HB.We performed comprehensive genomic, transcriptomic epigenomic characterization 159 clinically annotated samples from 113 HB, using high-throughput technologies.We discovered widespread epigenetic footprint that includes hyperediting tumor suppressor BLCAP concomitant genome-wide dysregulation RNA editing overexpression mainly non-coding genes oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, identified 2 clusters (Epi-CA, Epi-CB) distinct degrees DNA hypomethylation CpG island hypermethylation are associated C1/C2/C2B subtypes. Based on these findings, defined first molecular risk stratification (MRS-HB), which encompasses 3 main prognostic categories improves current clinical approach. The MRS-3 category (28%), by strong locus expression Epi-CB methylation features, was characterized CTNNB1 NFE2L2 mutations, progenitor-like phenotype aggressiveness. Finally, choline kinase alpha as promising target intermediate high-risk HBs, its inhibition cell lines patient-derived xenografts strongly abrogated growth.These findings provide detailed insight into features could be used improve approaches develop treatments HB.Hepatoblastoma childhood cancer has been understudied. We have cutting-edge technologies expand our knowledge this cancer. Our biological can management pave way development novel therapies