Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications.
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Carrillo-Reixach Juan, Torrens Laura, Simon-Coma Marina, Royo Laura, Domingo-Sàbat Montserrat, Abril-Fornaguera Jordi, Akers Nicholas, Sala Margarita, Ragull Sonia, Arnal Magdalena, Villalmanzo Núria, Cairo Stefano, Villanueva Alberto, Kappler Roland, Garrido Marta, Guerra Laura, Sábado Constantino, Guillén Gabriela, Mallo Mar, Piñeyro David, Vázquez-Vitali María, Kuchuk Olga, Mateos María Elena, Ramírez Gema, Santamaría Manuel López, Mozo Yasmina, Soriano Aroa, Grotzer Michael, Branchereau Sophie, de Andoin Nagore García, López-Ibor Blanca, López-Almaraz Ricardo, Salinas José Antonio, Torres Bárbara, Hernández Francisco, Uriz José Javier, Fabre Monique, Blanco Julià, Paris Claudia, Bajčiová Viera, Laureys Geneviève, Masnou Helena, Clos Ariadna, Belendez Cristina, Guettier Catherine, Sumoy Lauro, Planas Ramón, Jordà Mireia, Nonell Lara, Czauderna Piotr, Morland Bruce, Sia Daniela, Losic Bojan, Buendia Marie Annick, Sarrias Maria Rosa, Llovet Josep M, Armengol Carolina
Аннотация
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.