Published March 30, 2020 | Version v1
Journal article Open

Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications

  • 1. Germans Trias i Pujol Research Institute (IGTP)
  • 2. , Icahn School of Medicine at Mount Sinai
  • 3. Universitat de Barcelona
  • 4. CIBER, Hepatic and Digestive Diseases
  • 5. Hospital del Mar Medical Research Institute
  • 6. PMPPC, IGTP
  • 7. XenTech
  • 8. Catalan Institute of Oncology (ICO)
  • 9. Ludwig-Maximilians-University Munich
  • 10. Hospital Vall d'Hebron, Pathology Department
  • 11. University Hospital La Paz
  • 12. Hospital Vall d'Hebron, Pediatric Oncology Department
  • 13. Hospital Vall d'Hebron, Pediatric Surgery Department
  • 14. Universitat Autònoma de Barcelona
  • 15. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
  • 16. University Hospital Reina Sofía
  • 17. University Hospital Universitario Virgen del Rocío
  • 18. Institut de Recerca Hospital Vall d'Hebron (VHIR)
  • 19. University Children's Hospital Zurich
  • 20. Bicêtre Hospital
  • 21. Hospital Universitario Donostia
  • 22. HM Montepríncipe Hospital
  • 23. Hospital Universitario Cruces
  • 24. Hospital Universitari Son Espases
  • 25. University Hospital La Fe
  • 26. University Hospital La Paz,
  • 27. Hôpital Universitaire Necker-Enfants Malades
  • 28. University of Vic - Central University of Catalonia
  • 29. Hospital Luis Calvo Mackenna
  • 30. Childrens University Hospital Brno
  • 31. Ghent University Hospital
  • 32. Hospital Universitari Germans Trias i Pujol Hospital
  • 33. Hospital Gregorio Marañón
  • 34. Medical University of Gdansk
  • 35. Birmingham Women's and Children's Hospital
  • 36. Icahn School of Medicine at Mount Sinai
  • 37. Paul-Brousse Hospital, Hepatobiliary Centre


Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Here we sought to increase knowledge of HB pathobiology in an effort to move towards precision medicine. To this end, we used high-throughput technologies to identify new biomarkers and therapeutic targets for HB patients with poor prognosis METHODS: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically-annotated samples from 113 HB patients RESULTS: We discovered an unprecedented 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 two epigenomic clusters (Epi-CA, Epi-CB) with distinct degree 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 three 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 since its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth CONCLUSIONS: Our findings expand our knowledge about the molecular features of HB and may contribute to improve current clinical stratification approaches and treatments to increase the survival of patients with HB.


22- Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications.pdf

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