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

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

doi:10.1038/s41698-020-0125-y

Abstract

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.

Highlights

Hepatoblastoma is the most common pediatric liver cancer that mainly affects young children[1]
Was the ODC1 protein level decreased in NQO1-low hepatoblastoma samples compared with NQO1-high samples, despite the comparable high ODC1 mRNA expression (Supplementary Fig. 12a–c), but we observed a reduction in ODC1 protein levels in HepG2 cells after NQO1 inhibition (Supplementary Fig. 12d, e); these results indicate that NQO1 plays an important role in the stabilization of the ODC1 protein in hepatoblastoma cells
We present a genome-wide molecular portrait of hepatoblastoma characterized by uniformly upregulated Wnt reported as a poor prognostic factor in hepatoblastoma in a previous study[8], the mechanism of high NQO1 expression has not been clarified except for activating mutation of NEF2L2, a signaling pathway and novel DNA methylation clusters which transcription factor upstream of NQO1

Summary

Introduction

Hepatoblastoma is the most common pediatric liver cancer that mainly affects young children[1]. This disease is clinically heterogeneous, and the treatment outcome of hepatoblastoma has improved with the overall survival reaching ~80%2, the prognosis of high-risk cases with unfavorable prognostic factors is still poor despite high-intensity therapy[3]. As intensification of the chemotherapy applied to such high-risk cases is reaching a limit, novel therapeutic approaches based on the understanding of the biological mechanisms are required to overcome high-risk hepatoblastoma. Cairo et al described the molecular classification of hepatoblastoma into two subclasses, C1 and C2, using a 16-gene signature, with C2 being a group with poor prognosis in the cohort[7]. Sumazin et al revealed that the classification was not prognostically predictive in another cohort[9]

Methods

Results

Conclusion