Juan Carrillo-Reixach1, Laura Torrens2, Marina Simon-Coma3, Laura Royo1, Montserrat Domingo-Sàbat1, Jordi Abril-Fornaguera2, Nicholas Akers4, Margarita Sala5, Sonia Ragull1, Magdalena Arnal6, Núria Villalmanzo7, Stefano Cairo8, Alberto Villanueva9, Roland Kappler10, Marta Garrido11, Laura Guerra12, Constantino Sábado13, Gabriela Guillén14, Mar Mallo15, David Piñeyro16, María Vázquez-Vitali1, Olga Kuchuk17, María Elena Mateos18, Gema Ramírez19, Manuel López Santamaría20, Yasmina Mozo21, Aroa Soriano22, Michael Grotzer23, Sophie Branchereau24, Nagore García de Andoin25, Blanca López-Ibor26, Ricardo López-Almaraz27, José Antonio Salinas28, Bárbara Torres29, Francisco Hernández20, José Javier Uriz25, Monique Fabre30, Julià Blanco31, Claudia Paris32, Viera Bajčiová33, Geneviève Laureys34, Helena Masnou35, Ariadna Clos35, Cristina Belendez36, Catherine Guettier24, Lauro Sumoy16, Ramón Planas37, Mireia Jordà38, Lara Nonell6, Piotr Czauderna39, Bruce Morland40, Daniela Sia17, Bojan Losic41, Marie Annick Buendia42, Maria Rosa Sarrias43, Josep M Llovet44, Carolina Armengol45. 1. Childhood Liver Oncology Group, Germans Trias i Pujol Research Institute (IGTP), Program for Predictive and Personalized Medicine of Cancer (PMPPC), Badalona, Spain. 2. Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Translational research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. 3. Childhood Liver Oncology Group, Germans Trias i Pujol Research Institute (IGTP), Program for Predictive and Personalized Medicine of Cancer (PMPPC), Badalona, Spain; CIBER, Hepatic and Digestive Diseases, Barcelona, Spain. 4. Translational research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA. 5. CIBER, Hepatic and Digestive Diseases, Barcelona, Spain; Gastroenterology Department, Hospital Universitari Germans Trias i Pujol Hospital, Badalona, Spain; Gastroenterology Department, Hospital Universitari Josep Trueta, Girona, Spain. 6. MARGenomics, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. 7. PMPPC, IGTP, Badalona, Spain. 8. XenTech, Evry, France; Instituto di Ricerca Pediatrica, Corso Stati Uniti 4, Padova, Italy. 9. Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute, L'Hospitalet del Llobregat, Barcelona, Spain. 10. Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstr. 2a, 80337 Munich, Germany. 11. Hospital Vall d'Hebron, Pathology Department, Barcelona, Spain. 12. University Hospital La Paz, Pathology Department, Madrid, Spain. 13. Hospital Vall d'Hebron, Pediatric Oncology Department, Barcelona, Spain. 14. Hospital Vall d'Hebron, Pediatric Surgery Department, Barcelona, Spain. 15. MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. 16. High Content Genomics and Bioinformatics Unit, PMPPC, IGTP, Badalona, Spain. 17. Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA. 18. Pediatric Oncology Unit, Department of Pediatrics, University Hospital Reina Sofía, Córdoba, Spain. 19. University Hospital Universitario Virgen del Rocío, Pediatric Oncology Department, Sevilla, Spain. 20. University Hospital La Paz, Pediatric Surgery Department, Madrid, Spain. 21. University Hospital La Paz, Pediatric Oncology Department, Madrid, Spain. 22. Biomedical Research in Cancer Stem Cells Group, Pathology Department, Institut de Recerca Hospital Vall d'Hebron (VHIR), Barcelona, Spain. 23. Department of Pediatric Oncology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland. 24. Bicêtre Hospital, Le Kremlin-Bicêtre, France. 25. Pediatric Oncology, Hospital Universitario Donostia, Doctor Begiristain Kalea, 117, 20080, Donostia, Spain. 26. Department of Pediatric Hematology and Oncology, HM Montepríncipe Hospital, Boadilla del Monte, Madrid, Spain. 27. Pediatric Oncology and Hematology, Hospital Universitario Cruces, Bilbao, Spain. 28. Division of Hematology-Oncology, Department of Pediatrics, Hospital Universitari Son Espases, Palma de Mallorca, Spain. 29. Medical Oncology Department, Pediatric Oncology Department, University Hospital La Fe, Valencia, Spain. 30. Department of Pathology, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Paris, France. 31. IrsiCaixa AIDS Research Institute, IGTP, Badalona, Catalonia, Spain; University of Vic - Central University of Catalonia, Vic, Spain. 32. Stem Cell Transplant Unit, Hospital Luis Calvo Mackenna, Santiago, Chile. 33. Department of Pediatric Oncology, Childrens University Hospital Brno, Brno, Czech. 34. Department of Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium. 35. Gastroenterology Department, Hospital Universitari Germans Trias i Pujol Hospital, Badalona, Spain. 36. Oncohematology Service, Hospital Gregorio Marañón, Madrid, Spain. 37. CIBER, Hepatic and Digestive Diseases, Barcelona, Spain; Gastroenterology Department, Hospital Universitari Germans Trias i Pujol Hospital, Badalona, Spain. 38. PMPPC, IGTP, Badalona, Spain; Consortium for the Study of Thyroid Cancer, CECaT, Barcelona, Spain. 39. Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland. 40. Department of Oncology, Birmingham Women's and Children's Hospital, Birmingham, UK. 41. Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA; Graduate School of Biomedical Sciences, One Gustave L. Levy Place, Box 1022, New York, NY; Tisch Cancer Institute, Cancer Immunology Program, Icahn School of Medicine at Mount Sinai, New York, NY; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY. 42. INSERM, UMR 1193, Paul-Brousse Hospital, Hepatobiliary Centre, Villejuif, France. 43. CIBER, Hepatic and Digestive Diseases, Barcelona, Spain; Innate Immunity Group, IGTP, Badalona, Spain. 44. Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Translational research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. 45. Childhood Liver Oncology Group, Germans Trias i Pujol Research Institute (IGTP), Program for Predictive and Personalized Medicine of Cancer (PMPPC), Badalona, Spain; CIBER, Hepatic and Digestive Diseases, Barcelona, Spain. Electronic address: carmengol@igtp.cat.
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.
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.