Genetic and epigenetic basis of hepatoblastoma diversity.

Abstract

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.

• Authors: Genta Nagae, Shogo Yamamoto, Masashi Fujita, Takanori Fujita, Aya Nonaka, Takayoshi Umeda, Shiro Fukuda, Kenji Tatsuno, Kazuhiro Maejima, Akimasa Hayashi, Sho Kurihara, Masato Kojima, Tomoro Hishiki, Kenichiro Watanabe, Kohmei Ida, Michihiro Yano, Yoko Hiyama, Yukichi Tanaka, Takeshi Inoue, Hiroki Ueda, Hidewaki Nakagawa, Hiroyuki Aburatani, Eiso Hiyama
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 5423 (09 20 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34538872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• beta Catenin
• Telomerase

Topics

• 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)