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<p>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 <i>TP53</i> 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 <i>TP53</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Yoshinori Uchihara,
  • Keiji Tasaka,
  • Takashi Mikami,
  • Yosuke Yamada,
  • Hiroaki Ito,
  • Hajime Okita,
  • Ryunosuke Tojo,
  • Ryo Akazawa,
  • Kiyotaka Isobe,
  • Tatsuya Kamitori,
  • Masahiko Nishitani-Isa,
  • Hirohito Kubota,
  • Satoshi Saida,
  • Itaru Kato,
  • Tatsuya Okamoto,
  • Eri Ogawa,
  • Hideaki Okajima,
  • Yukichi Tanaka,
  • Takako Yoshioka,
  • Nobuyuki Kakiuchi,
  • Yuichi Shiraishi,
  • Tetsuya Takimoto,
  • Shugo Komatsu,
  • Mitsutaka Shiota,
  • Kazuko Kudo,
  • Hiroyuki Fujisaki,
  • Masahiro Sekiguchi,
  • Yoshiyuki Takahashi,
  • Mamoru Ito,
  • Tatsutoshi Nakahata,
  • Hironori Haga,
  • Eiso Hiyama,
  • Seishi Ogawa,
  • Katsutsugu Umeda,
  • Junko Takita

摘要

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.