Integrated Molecular Characterization of Sarcomatoid Hepatocellular Carcinoma

Sun, Rong-Qi; Ye, Yu-Hang; Xu, Ye; Wang, Bo; Pan, Si-Yuan; Li, Ning; Chen, Long; Pan, Jing-Yue; Hu, Zhi-Qiang; Fan, Jia; Zhou, Zheng-Jun; Zhou, Jian; Song, Cheng-Li; Zhou, Shao-Lai

doi:.0..

Original Article

Integrated Molecular Characterization of Sarcomatoid Hepatocellular Carcinoma

Rong-Qi Sun^1,2, Yu-Hang Ye^1,2, Ye Xu^1,2, Bo Wang³, Si-Yuan Pan, Ning Li^1,2, Long Chen^1,2, Jing-Yue Pan^1,2, Zhi-Qiang Hu^1,2, Jia Fan^1,2, Zheng-Jun Zhou^1,2, Jian Zhou^1,2, Cheng-Li Song⁴, Shao-Lai Zhou^1,2

¹Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, China
²Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
³Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, Dalian, China
⁴Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China

Correspondence :

Zheng-Jun Zhou ,
Email: zhouzhengjun1221@126.com
Jian Zhou ,
Email: zhou.jian@zs-hospital.sh.cn
Cheng-Li Song ,
Email: songchengli@dmu.edu.cn
Shao-Lai Zhou ,
Email: zhoushaolai99@sina.com

Received: August 21, 2024 Revised: November 15, 2024 Accepted: December 6, 2024
*Rong-Qi Sun, Yu-Hang Ye, Ye Xu and Bo Wang contributed equally to this work.

ABSTRACT

Background
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.

KeyWords: Sarcomatoid hepatocellular carcinoma; multiomics; ARID2; Epithelial–mesenchymal transition