Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications

Juan Carrillo-Reixach, Laura Torrens, Marina Simon-Coma, Laura Royo, Montserrat Domingo-Sàbat, Jordi Abril-Fornaguera, 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 PiñeyroMaría Vázquez-Vitali, Olga Kuchuk, María Elena Mateos, Gema Ramírez, Manuel López Santamaría, Yasmina Mozo, Aroa Soriano, Michael Grotzer, Sophie Branchereau, Nagore García de Andoin, Blanca López-Ibor, Ricardo López-Almaraz, 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

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish
Pages (from-to)328-341
Number of pages14
JournalJournal of Hepatology
Volume73
Issue number2
DOIs
StatePublished - Aug 2020

Keywords

  • 14q32
  • BLCAP
  • CHKA
  • DLK1-DIO3 locus
  • Hepatoblastoma (HB)
  • Molecular risk stratification
  • Prognostic biomarker
  • RNA editing

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