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

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 methy...

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Autores principales: Sekiguchi, Masahiro, Seki, Masafumi, Kawai, Tomoko, Yoshida, Kenichi, Yoshida, Misa, Isobe, Tomoya, Hoshino, Noriko, Shirai, Ryota, Tanaka, Mio, Souzaki, Ryota, Watanabe, Kentaro, Arakawa, Yuki, Nannya, Yasuhito, Suzuki, Hiromichi, Fujii, Yoichi, Kataoka, Keisuke, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Shimamura, Teppei, Sato, Yusuke, Sato-Otsubo, Aiko, Kimura, Shunsuke, Kubota, Yasuo, Hiwatari, Mitsuteru, Koh, Katsuyoshi, Hayashi, Yasuhide, Kanamori, Yutaka, Kasahara, Mureo, Kohashi, Kenichi, Kato, Motohiro, Yoshioka, Takako, Matsumoto, Kimikazu, Oka, Akira, Taguchi, Tomoaki, Sanada, Masashi, Tanaka, Yukichi, Miyano, Satoru, Hata, Kenichiro, Ogawa, Seishi, Takita, Junko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341754/
https://www.ncbi.nlm.nih.gov/pubmed/32656360
http://dx.doi.org/10.1038/s41698-020-0125-y
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author Sekiguchi, Masahiro
Seki, Masafumi
Kawai, Tomoko
Yoshida, Kenichi
Yoshida, Misa
Isobe, Tomoya
Hoshino, Noriko
Shirai, Ryota
Tanaka, Mio
Souzaki, Ryota
Watanabe, Kentaro
Arakawa, Yuki
Nannya, Yasuhito
Suzuki, Hiromichi
Fujii, Yoichi
Kataoka, Keisuke
Shiraishi, Yuichi
Chiba, Kenichi
Tanaka, Hiroko
Shimamura, Teppei
Sato, Yusuke
Sato-Otsubo, Aiko
Kimura, Shunsuke
Kubota, Yasuo
Hiwatari, Mitsuteru
Koh, Katsuyoshi
Hayashi, Yasuhide
Kanamori, Yutaka
Kasahara, Mureo
Kohashi, Kenichi
Kato, Motohiro
Yoshioka, Takako
Matsumoto, Kimikazu
Oka, Akira
Taguchi, Tomoaki
Sanada, Masashi
Tanaka, Yukichi
Miyano, Satoru
Hata, Kenichiro
Ogawa, Seishi
Takita, Junko
author_facet Sekiguchi, Masahiro
Seki, Masafumi
Kawai, Tomoko
Yoshida, Kenichi
Yoshida, Misa
Isobe, Tomoya
Hoshino, Noriko
Shirai, Ryota
Tanaka, Mio
Souzaki, Ryota
Watanabe, Kentaro
Arakawa, Yuki
Nannya, Yasuhito
Suzuki, Hiromichi
Fujii, Yoichi
Kataoka, Keisuke
Shiraishi, Yuichi
Chiba, Kenichi
Tanaka, Hiroko
Shimamura, Teppei
Sato, Yusuke
Sato-Otsubo, Aiko
Kimura, Shunsuke
Kubota, Yasuo
Hiwatari, Mitsuteru
Koh, Katsuyoshi
Hayashi, Yasuhide
Kanamori, Yutaka
Kasahara, Mureo
Kohashi, Kenichi
Kato, Motohiro
Yoshioka, Takako
Matsumoto, Kimikazu
Oka, Akira
Taguchi, Tomoaki
Sanada, Masashi
Tanaka, Yukichi
Miyano, Satoru
Hata, Kenichiro
Ogawa, Seishi
Takita, Junko
author_sort Sekiguchi, Masahiro
collection PubMed
description 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.
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spelling pubmed-73417542020-07-09 Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets Sekiguchi, Masahiro Seki, Masafumi Kawai, Tomoko Yoshida, Kenichi Yoshida, Misa Isobe, Tomoya Hoshino, Noriko Shirai, Ryota Tanaka, Mio Souzaki, Ryota Watanabe, Kentaro Arakawa, Yuki Nannya, Yasuhito Suzuki, Hiromichi Fujii, Yoichi Kataoka, Keisuke Shiraishi, Yuichi Chiba, Kenichi Tanaka, Hiroko Shimamura, Teppei Sato, Yusuke Sato-Otsubo, Aiko Kimura, Shunsuke Kubota, Yasuo Hiwatari, Mitsuteru Koh, Katsuyoshi Hayashi, Yasuhide Kanamori, Yutaka Kasahara, Mureo Kohashi, Kenichi Kato, Motohiro Yoshioka, Takako Matsumoto, Kimikazu Oka, Akira Taguchi, Tomoaki Sanada, Masashi Tanaka, Yukichi Miyano, Satoru Hata, Kenichiro Ogawa, Seishi Takita, Junko NPJ Precis Oncol Article 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. Nature Publishing Group UK 2020-07-07 /pmc/articles/PMC7341754/ /pubmed/32656360 http://dx.doi.org/10.1038/s41698-020-0125-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sekiguchi, Masahiro
Seki, Masafumi
Kawai, Tomoko
Yoshida, Kenichi
Yoshida, Misa
Isobe, Tomoya
Hoshino, Noriko
Shirai, Ryota
Tanaka, Mio
Souzaki, Ryota
Watanabe, Kentaro
Arakawa, Yuki
Nannya, Yasuhito
Suzuki, Hiromichi
Fujii, Yoichi
Kataoka, Keisuke
Shiraishi, Yuichi
Chiba, Kenichi
Tanaka, Hiroko
Shimamura, Teppei
Sato, Yusuke
Sato-Otsubo, Aiko
Kimura, Shunsuke
Kubota, Yasuo
Hiwatari, Mitsuteru
Koh, Katsuyoshi
Hayashi, Yasuhide
Kanamori, Yutaka
Kasahara, Mureo
Kohashi, Kenichi
Kato, Motohiro
Yoshioka, Takako
Matsumoto, Kimikazu
Oka, Akira
Taguchi, Tomoaki
Sanada, Masashi
Tanaka, Yukichi
Miyano, Satoru
Hata, Kenichiro
Ogawa, Seishi
Takita, Junko
Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
title Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
title_full Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
title_fullStr Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
title_full_unstemmed Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
title_short Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
title_sort integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341754/
https://www.ncbi.nlm.nih.gov/pubmed/32656360
http://dx.doi.org/10.1038/s41698-020-0125-y
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