Genetic and epigenetic basis of hepatoblastoma diversity

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 and Eiso Hiyama ()
Additional contact information
Genta Nagae: the University of Tokyo
Shogo Yamamoto: the University of Tokyo
Masashi Fujita: RIKEN Center for Integrative Medical Sciences
Takanori Fujita: the University of Tokyo
Aya Nonaka: the University of Tokyo
Takayoshi Umeda: the University of Tokyo
Shiro Fukuda: the University of Tokyo
Kenji Tatsuno: the University of Tokyo
Kazuhiro Maejima: RIKEN Center for Integrative Medical Sciences
Akimasa Hayashi: the University of Tokyo
Sho Kurihara: Hiroshima University Hospital
Masato Kojima: Hiroshima University Hospital
Tomoro Hishiki: Chiba University Graduate School of Medicine
Kenichiro Watanabe: Shizuoka Children’s Hospital
Kohmei Ida: Teikyo University Mizonokuchi Hospital
Michihiro Yano: Akita University Hospital
Yoko Hiyama: Hiroshima University
Yukichi Tanaka: Kanagawa Children’s Medical Center
Takeshi Inoue: Osaka City General Hospital
Hiroki Ueda: the University of Tokyo
Hidewaki Nakagawa: RIKEN Center for Integrative Medical Sciences
Hiroyuki Aburatani: the University of Tokyo
Eiso Hiyama: Hiroshima University Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25430-9

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