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Peer-reviewedCC BY-NC-ND 4.0NPJ Precision Oncology

Stepwise malignant transformation from MHL to UESL via activation of C19MC and loss of TP53

  • Yoshinori Uchihara1
  • Keiji Tasaka1,2
  • Takashi Mikami1
  • Yosuke Yamada3
  • Hiroaki Ito3
  • Hajime Okita4
  • Ryunosuke Tojo1
  • Ryo Akazawa1
  • Kiyotaka Isobe1
  • Tatsuya Kamitori1
  • Masahiko Nishitani-Isa1
  • Hirohito Kubota1
23 more authors
  • Satoshi Saida1
  • Itaru Kato1
  • Tatsuya Okamoto5
  • Eri Ogawa5
  • Hideaki Okajima5
  • Yukichi Tanaka6
  • Takako Yoshioka7
  • Nobuyuki Kakiuchi8,9
  • Yuichi Shiraishi10
  • Tetsuya Takimoto11
  • Shugo Komatsu12
  • Mitsutaka Shiota13
  • Kazuko Kudo14
  • Hiroyuki Fujisaki15
  • Masahiro Sekiguchi16
  • Yoshiyuki Takahashi17
  • Mamoru Ito18
  • Tatsutoshi Nakahata18
  • Hironori Haga3
  • Eiso Hiyama19
  • Seishi Ogawa8,20,21
  • Katsutsugu Umeda1,22
  • Junko Takita1
22 affiliations
  1. 1Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  2. 2Department of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan
  3. 3Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  4. 4Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan
  5. 5Department of Pediatric Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  6. 6Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan
  7. 7Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
  8. 8Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  9. 9The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan
  10. 10Division of Genome Analysis Platform Development, National Cancer Center Institute, Tokyo, Japan
  11. 11Department of Childhood Cancer Data Management, Clinical Research Center, National Center for Child Health and Development, Tokyo, Japan
  12. 12Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
  13. 13Department of Pediatrics, Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-Kofukai, Osaka, Japan
  14. 14Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan
  15. 15Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan
  16. 16Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  17. 17Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
  18. 18Laboratory Animal Research Department, Central Institute for Experimental Medicine and Life Science, Kawasaki, Japan
  19. 19Department of Biomedical Science, Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
  20. 20Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
  21. 21Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden
  22. 22Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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Abstract

Undifferentiated embryonal sarcoma of the liver (UESL) and mesenchymal hamartoma of the liver (MHL) are rare pediatric liver tumors with poorly understood oncogenic mechanisms. Although UESL occasionally arises from MHL, the relationship between these entities remains elusive. Here, we conducted comprehensive multi-omics profiling of 18 UESL and six MHL cases, and identified structural variants (SVs) involving the C19MC miRNA cluster in all tumors, resulting in robust overexpression of C19MC miRNAs. While mutations in TP53 were detected in all UESL samples, they were absent from MHL. Functional studies demonstrated that overexpression of C19MC miRNAs alone was insufficient for transformation, but acted synergistically with TP53 loss to drive oncogenicity. Spatial transcriptomics performed on a tumor sample containing a composite MHL-UESL lesion revealed pseudo-temporal gene expression trajectories and clonal diversification. Collectively, these findings delineate a stepwise malignant transformation from MHL to UESL, and reveal the underlying cooperative genetic events.

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Cite

BibTeXRIS
BibTeX
@article{uchihara2026stepwise,
  title = {{Stepwise malignant transformation from MHL to UESL via activation of C19MC and loss of TP53}},
  author = {Yoshinori Uchihara and Keiji Tasaka and Takashi Mikami and Yosuke Yamada and Hiroaki Ito and Hajime Okita and Ryunosuke Tojo and Ryo Akazawa and Kiyotaka Isobe and Tatsuya Kamitori and Masahiko Nishitani-Isa and Hirohito Kubota and Satoshi Saida and Itaru Kato and Tatsuya Okamoto and Eri Ogawa and Hideaki Okajima and Yukichi Tanaka and Takako Yoshioka and Nobuyuki Kakiuchi and Yuichi Shiraishi and Tetsuya Takimoto and Shugo Komatsu and Mitsutaka Shiota and Kazuko Kudo and Hiroyuki Fujisaki and Masahiro Sekiguchi and Yoshiyuki Takahashi and Mamoru Ito and Tatsutoshi Nakahata and Hironori Haga and Eiso Hiyama and Seishi Ogawa and Katsutsugu Umeda and Junko Takita},
  journal = {NPJ Precision Oncology},
  year = {2026},
  month = jul,
  doi = {10.1038/s41698-026-01563-2},
  url = {https://doi.org/10.1038/s41698-026-01563-2},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Stepwise malignant transformation from MHL to UESL via activation of C19MC and loss of TP53
AU  - Yoshinori Uchihara
AU  - Keiji Tasaka
AU  - Takashi Mikami
AU  - Yosuke Yamada
AU  - Hiroaki Ito
AU  - Hajime Okita
AU  - Ryunosuke Tojo
AU  - Ryo Akazawa
AU  - Kiyotaka Isobe
AU  - Tatsuya Kamitori
AU  - Masahiko Nishitani-Isa
AU  - Hirohito Kubota
AU  - Satoshi Saida
AU  - Itaru Kato
AU  - Tatsuya Okamoto
AU  - Eri Ogawa
AU  - Hideaki Okajima
AU  - Yukichi Tanaka
AU  - Takako Yoshioka
AU  - Nobuyuki Kakiuchi
AU  - Yuichi Shiraishi
AU  - Tetsuya Takimoto
AU  - Shugo Komatsu
AU  - Mitsutaka Shiota
AU  - Kazuko Kudo
AU  - Hiroyuki Fujisaki
AU  - Masahiro Sekiguchi
AU  - Yoshiyuki Takahashi
AU  - Mamoru Ito
AU  - Tatsutoshi Nakahata
AU  - Hironori Haga
AU  - Eiso Hiyama
AU  - Seishi Ogawa
AU  - Katsutsugu Umeda
AU  - Junko Takita
PY  - 2026
DA  - 2026/07/14
JO  - NPJ Precision Oncology
DO  - 10.1038/s41698-026-01563-2
UR  - https://doi.org/10.1038/s41698-026-01563-2
AB  - Undifferentiated embryonal sarcoma of the liver (UESL) and mesenchymal hamartoma of the liver (MHL) are rare pediatric liver tumors with poorly understood oncogenic mechanisms. Although UESL occasionally arises from MHL, the relationship between these entities remains elusive. Here, we conducted comprehensive multi-omics profiling of 18 UESL and six MHL cases, and identified structural variants (SVs) involving the C19MC miRNA cluster in all tumors, resulting in robust overexpression of C19MC miRNAs. While mutations in TP53 were detected in all UESL samples, they were absent from MHL. Functional studies demonstrated that overexpression of C19MC miRNAs alone was insufficient for transformation, but acted synergistically with TP53 loss to drive oncogenicity. Spatial transcriptomics performed on a tumor sample containing a composite MHL-UESL lesion revealed pseudo-temporal gene expression trajectories and clonal diversification. Collectively, these findings delineate a stepwise malignant transformation from MHL to UESL, and reveal the underlying cooperative genetic events.
SN  - 2397-768X
ER  -