Genetic and epigenetic basis of hepatoblastoma diversity.

Child, Preschool Chromatin Immunoprecipitation Sequencing / methods Cohort Studies DNA Copy Number Variations DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Hepatoblastoma / genetics Humans Infant Kaplan-Meier Estimate Liver Neoplasms / genetics Male Mutation Promoter Regions, Genetic / genetics Telomerase / genetics Exome Sequencing / methods beta Catenin / genetics

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
20 09 2021

Historique:

received: 17 09 2020

accepted: 06 08 2021

entrez: 20 9 2021

pubmed: 21 9 2021

medline: 21 10 2021

Statut: epublish

Résumé

Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their "cell of origin" derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.

Identifiants

DOI: 10.1038/s41467-021-25430-9 PMID: 34538872 PMC: PMC8450290

pubmed: 34538872

doi: 10.1038/s41467-021-25430-9

pii: 10.1038/s41467-021-25430-9

pmc: PMC8450290

doi:

Substances chimiques

beta Catenin 0

Telomerase EC 2.7.7.49

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

5423

Informations de copyright

Références

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