Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets

Masahiro Sekiguchi, Masafumi Seki, Tomoko Kawai, Kenichi Yoshida, Misa Yoshida, Tomoya Isobe, Noriko Hoshino, Ryota Shirai, Mio Tanaka, Ryota Souzaki, Kentaro Watanabe, Yuki Arakawa, Yasuhito Nannya, Hiromichi Suzuki, Yoichi Fujii, Keisuke Kataoka, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Teppei ShimamuraYusuke Sato, Aiko Sato-Otsubo, Shunsuke Kimura, Yasuo Kubota, Mitsuteru Hiwatari, Katsuyoshi Koh, Yasuhide Hayashi, Yutaka Kanamori, Mureo Kasahara, Kenichi Kohashi, Motohiro Kato, Takako Yoshioka, Kimikazu Matsumoto, Akira Oka, Tomoaki Taguchi, Masashi Sanada, Yukichi Tanaka, Satoru Miyano, Kenichiro Hata, Seishi Ogawa, Junko Takita

研究成果: Article査読

16 被引用数 (Scopus)

抄録

Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of NQO1 and ODC1. Inhibition of NQO1 and ODC1 in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.

本文言語English
論文番号20
ジャーナルnpj Precision Oncology
4
1
DOI
出版ステータスPublished - 2020 12月 1
外部発表はい

ASJC Scopus subject areas

  • 癌研究
  • 腫瘍学

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