Clin Mol Hepatol.
2025 Apr;31(2):426-444. 10.3350/cmh.2024.0686.
Integrated molecular characterization of sarcomatoid hepatocellular carcinoma
- Sun RQ1,2
- Ye YH1,2
- Xu Y1,2
- Wang B3
- Pan SY1,2
- Li N1,2
- Chen L1,2
- Pan JY1,2
- Hu ZQ1,2
- Fan J1,2
- Zhou ZJ
1,2 - Zhou J1,2
- Song CL4
- Zhou SL1,2
- Affiliations
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- 1Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- 2Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- 3Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, Dalian, China
- 4Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- KMID: 2566968
- DOI: http://doi.org/10.3350/cmh.2024.0686
Abstract
- Backgrounds/Aims
Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated.
Methods
In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs.
Results
Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment.
Conclusions
We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.
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