Journal article Open Access
Carrillo-Reixach, J.; Torrens, L.; Simon-Coma, M.; Royo, L.; Domingo-Sàbat, M.; Abril-Fornaguera, J.; Akers, N.; Sala, M.; Ragull, S.; Arnal, M.; Villalmanzo, N.; Cairo, S.; Villanueva, A.; Kappler, R.; Garrido, M.; Guerra, L.; Sábado, C.; Guillén, G.; Mallo, M.; Piñeyro, D.; Vázquez-Vitali, M.; Kuchuk, O.; Mateos, M.; Ramírez, G.; Santamaría, M.; Mozo, Y.; Soriano, A.; Grotzer, M.; Branchereau, S.; Andoin, G.; López-Ibor, B.; López-Almaraz, R.; Salinas, J.; Torres, B.; Hernández, F.; Uriz, J.; Fabre, M.; Blanco, J.; Paris, C.; Bajciová, V.; Laureys, G.; Masnou, H.; Clos, A.; Belendez, C.; Guettier, C.; Sumoy, L.; Planas, R.; Jordà, M.; Nonell, L.; Czauderna, P.; Morland, B.; Sia, D.; Losic, B.; Buendia, M.; Sarrias, M.; Llovet, J.; Armengol, C.
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