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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,...
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.
Grantová podpora
C9380/A26813
Cancer Research UK - United Kingdom
P30 CA196521
NCI NIH HHS - United States
Odkazy
PubMed
32240714
DOI
10.1016/j.jhep.2020.03.025
Knihovny.cz E-zdroje
- MeSH
- beta-katenin genetika MeSH
- cholinkinasa * antagonisté a inhibitory metabolismus MeSH
- epigeneze genetická MeSH
- hepatoblastom * genetika metabolismus mortalita patologie MeSH
- hodnocení rizik metody MeSH
- kojenec MeSH
- lidé MeSH
- membránové proteiny genetika MeSH
- metylace DNA MeSH
- nádorové biomarkery analýza MeSH
- nádorové proteiny genetika MeSH
- nádory jater * genetika metabolismus mortalita patologie MeSH
- objevování léků metody MeSH
- prognóza MeSH
- proteiny vázající vápník genetika MeSH
- rychlé screeningové testy MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
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
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 Oncology Birmingham Women's and Children's Hospital Birmingham UK
Department of Pediatric Oncology Childrens University Hospital Brno Brno Czech
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
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
Medical Oncology Department Pediatric Oncology Department University Hospital La Fe Valencia Spain
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
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
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
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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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