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Genetic and epigenetic basis of hepatoblastoma diversity

Author

Listed:
  • 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
    Kyorin University Faculty of Medicine)

  • 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
    Hiroshima University)

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.

Suggested Citation

  • Genta Nagae & Shogo Yamamoto & Masashi Fujita & Takanori Fujita & Aya Nonaka & Takayoshi Umeda & Shiro Fukuda & Kenji Tatsuno & Kazuhiro Maejima & Akimasa Hayashi & Sho Kurihara & Masato Kojima & Tomo, 2021. "Genetic and epigenetic basis of hepatoblastoma diversity," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25430-9
    DOI: 10.1038/s41467-021-25430-9
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    Cited by:

    1. Jill Pilet & Theo Z. Hirsch & Barkha Gupta & Amélie Roehrig & Guillaume Morcrette & Aurore Pire & Eric Letouzé & Brice Fresneau & Sophie Taque & Laurence Brugières & Sophie Branchereau & Christophe Ch, 2023. "Preneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Hanbing Song & Simon Bucher & Katherine Rosenberg & Margaret Tsui & Deviana Burhan & Daniel Hoffman & Soo-Jin Cho & Arun Rangaswami & Marcus Breese & Stanley Leung & María V. Pons Ventura & E. Alejand, 2022. "Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Funan He & Abhik M. Bandyopadhyay & Laura J. Klesse & Anna Rogojina & Sang H. Chun & Erin Butler & Taylor Hartshorne & Trevor Holland & Dawn Garcia & Korri Weldon & Luz-Nereida Perez Prado & Anne-Mari, 2023. "Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Amélie Roehrig & Theo Z. Hirsch & Aurore Pire & Guillaume Morcrette & Barkha Gupta & Charles Marcaillou & Sandrine Imbeaud & Christophe Chardot & Emmanuel Gonzales & Emmanuel Jacquemin & Masahiro Seki, 2024. "Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. Jie Fang & Shivendra Singh & Changde Cheng & Sivaraman Natarajan & Heather Sheppard & Ahmed Abu-Zaid & Adam D. Durbin & Ha Won Lee & Qiong Wu & Jacob Steele & Jon P. Connelly & Hongjian Jin & Wenan Ch, 2023. "Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma," Nature Communications, Nature, vol. 14(1), pages 1-27, December.

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