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Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications

J. Carrillo-Reixach, L. Torrens, M. Simon-Coma, L. Royo, M. Domingo-Sàbat, J. Abril-Fornaguera, N. Akers, M. Sala, S. Ragull, M. Arnal, N. Villalmanzo, S. Cairo, A. Villanueva, R. Kappler, M. Garrido, L. Guerra, C. Sábado, G. Guillén, M. Mallo,...

. 2020 ; 73 (2) : 328-341. [pub] 20200330

Jazyk angličtina Země Nizozemsko

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.

Perzistentní odkaz   https://www.medvik.cz/link/bmc22004872

Grantová podpora
C9380/A26813 Cancer Research UK - United Kingdom
P30 CA196521 NCI NIH HHS - United States

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.

Bicêtre Hospital Le Kremlin Bicêtre France

Biomedical Research in Cancer Stem Cells Group Pathology Department Institut de Recerca Hospital Vall d'Hebron Barcelona Spain

Chemoresistance and Predictive Factors Group Program Against Cancer Therapeutic Resistance Catalan Institute of Oncology Bellvitge Biomedical Research Institute L'Hospitalet del Llobregat Barcelona Spain

Childhood Liver Oncology Group Germans Trias i Pujol Research Institute Badalona Spain

CIBER Hepatic and Digestive Diseases Barcelona Spain

Consortium for the Study of Thyroid Cancer CECaT 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

Department of Oncology Birmingham Women's and Children's Hospital Birmingham UK

Department of Pathology Hôpital Universitaire Necker Enfants Malades Assistance Publique Hôpitaux de Paris and Université Paris Descartes Paris France

Department of Pediatric Hematology and Oncology HM Montepríncipe Hospital Boadilla del Monte Madrid Spain

Department of Pediatric Hematology Oncology and Hematopoietic Stem Cell Transplantation Ghent University Hospital Ghent Belgium

Department of Pediatric Oncology Childrens University Hospital Brno Brno Czech

Department of Pediatric Oncology University Children's Hospital Zurich University of Zurich Zurich Switzerland

Department of Pediatric Surgery Dr von Hauner Children's Hospital Ludwig Maximilians University Munich Lindwurmstr 2a 80337 Munich Germany

Department of Surgery and Urology for Children and Adolescents Medical University of Gdansk Gdansk Poland

Division of Hematology Oncology Department of Pediatrics Hospital Universitari Son Espases Palma de Mallorca Spain

Gastroenterology Department Hospital Universitari Germans Trias i Pujol Hospital Badalona Spain

Gastroenterology Department Hospital Universitari Josep Trueta Girona Spain

Graduate School of Biomedical Sciences One Gustave L Levy Place Box 1022 New York NY

High Content Genomics and Bioinformatics Unit PMPPC IGTP Badalona Spain

Hospital Vall d'Hebron Pathology Department Barcelona Spain

Hospital Vall d'Hebron Pediatric Oncology Department Barcelona Spain

Hospital Vall d'Hebron Pediatric Surgery Department Barcelona Spain

Icahn Institute for Data Science and Genomic Technology Icahn School of Medicine at Mount Sinai New York NY

Innate Immunity Group IGTP Badalona Spain

INSERM UMR 1193 Paul Brousse Hospital Hepatobiliary Centre Villejuif France

Institució Catalana de Recerca i Estudis Avançats Barcelona Spain

Instituto di Ricerca Pediatrica Corso Stati Uniti 4 Padova Italy

IrsiCaixa AIDS Research Institute IGTP Badalona Catalonia Spain

MARGenomics IMIM Barcelona Spain

MDS Research Group Josep Carreras Leukaemia Research Institute ICO Hospital Germans Trias i Pujol Universitat Autònoma de Barcelona Badalona Spain

Medical Oncology Department Pediatric Oncology Department University Hospital La Fe Valencia Spain

Mount Sinai Liver Cancer Program Divisions of Liver Diseases Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York USA

Oncohematology Service Hospital Gregorio Marañón Madrid Spain

Pediatric Oncology and Hematology Hospital Universitario Cruces Bilbao Spain

Pediatric Oncology Hospital Universitario Donostia Doctor Begiristain Kalea 117 20080 Donostia Spain

Pediatric Oncology Unit Department of Pediatrics University Hospital Reina Sofía Córdoba Spain

PMPPC IGTP Badalona Spain

Stem Cell Transplant Unit Hospital Luis Calvo Mackenna Santiago Chile

Tisch Cancer Institute Cancer Immunology Program Icahn School of Medicine at Mount Sinai New York NY

Translational research in Hepatic Oncology Liver Unit Institut d'Investigacions Biomèdiques August Pi i Sunyer Hospital Clínic Universitat de Barcelona Barcelona Spain

University Hospital La Paz Pathology Department Madrid Spain

University Hospital La Paz Pediatric Oncology Department Madrid Spain

University Hospital La Paz Pediatric Surgery Department Madrid Spain

University Hospital Universitario Virgen del Rocío Pediatric Oncology Department Sevilla Spain

University of Vic Central University of Catalonia Vic Spain

XenTech Evry France

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$a Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications / $c J. Carrillo-Reixach, L. Torrens, M. Simon-Coma, L. Royo, M. Domingo-Sàbat, J. Abril-Fornaguera, N. Akers, M. Sala, S. Ragull, M. Arnal, N. Villalmanzo, S. Cairo, A. Villanueva, R. Kappler, M. Garrido, L. Guerra, C. Sábado, G. Guillén, M. Mallo, D. Piñeyro, M. Vázquez-Vitali, O. Kuchuk, ME. Mateos, G. Ramírez, ML. Santamaría, Y. Mozo, A. Soriano, M. Grotzer, S. Branchereau, NG. de Andoin, B. López-Ibor, R. López-Almaraz, JA. Salinas, B. Torres, F. Hernández, JJ. Uriz, M. Fabre, J. Blanco, C. Paris, V. Bajčiová, G. Laureys, H. Masnou, A. Clos, C. Belendez, C. Guettier, L. Sumoy, R. Planas, M. Jordà, L. Nonell, P. Czauderna, B. Morland, D. Sia, B. Losic, MA. Buendia, MR. Sarrias, JM. Llovet, C. Armengol
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$a 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.
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$a Piñeyro, David $u High Content Genomics and Bioinformatics Unit, PMPPC, IGTP, Badalona, Spain
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$a Mozo, Yasmina $u University Hospital La Paz, Pediatric Oncology Department, Madrid, Spain
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$a Soriano, Aroa $u Biomedical Research in Cancer Stem Cells Group, Pathology Department, Institut de Recerca Hospital Vall d'Hebron (VHIR), Barcelona, Spain
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$a Grotzer, Michael $u Department of Pediatric Oncology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
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$a Branchereau, Sophie $u Bicêtre Hospital, Le Kremlin-Bicêtre, France
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$a de Andoin, Nagore García $u Pediatric Oncology, Hospital Universitario Donostia, Doctor Begiristain Kalea, 117, 20080, Donostia, Spain
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$a López-Almaraz, Ricardo $u Pediatric Oncology and Hematology, Hospital Universitario Cruces, Bilbao, Spain
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$a Salinas, José Antonio $u Division of Hematology-Oncology, Department of Pediatrics, Hospital Universitari Son Espases, Palma de Mallorca, Spain
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$a Torres, Bárbara $u Medical Oncology Department, Pediatric Oncology Department, University Hospital La Fe, Valencia, Spain
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$a Hernández, Francisco $u University Hospital La Paz, Pediatric Surgery Department, Madrid, Spain
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$a Uriz, José Javier $u Pediatric Oncology, Hospital Universitario Donostia, Doctor Begiristain Kalea, 117, 20080, Donostia, Spain
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$a Fabre, Monique $u Department of Pathology, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Paris, France
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$a Blanco, Julià $u IrsiCaixa AIDS Research Institute, IGTP, Badalona, Catalonia, Spain; University of Vic - Central University of Catalonia, Vic, Spain
700    1_
$a Paris, Claudia $u Stem Cell Transplant Unit, Hospital Luis Calvo Mackenna, Santiago, Chile
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$a Bajčiová, Viera $u Department of Pediatric Oncology, Childrens University Hospital Brno, Brno, Czech
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$a Laureys, Geneviève $u Department of Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
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$a Masnou, Helena $u Gastroenterology Department, Hospital Universitari Germans Trias i Pujol Hospital, Badalona, Spain
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$a Clos, Ariadna $u Gastroenterology Department, Hospital Universitari Germans Trias i Pujol Hospital, Badalona, Spain
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$a Belendez, Cristina $u Oncohematology Service, Hospital Gregorio Marañón, Madrid, Spain
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$a Guettier, Catherine $u Bicêtre Hospital, Le Kremlin-Bicêtre, France
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$a Nonell, Lara $u MARGenomics, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
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