Oncogenic pathways refine a new perspective on the classification of hepatocellular carcinoma

Yuyuan Zhang; Zaoqu Liu; Jie Li; Bailu Wu; Xin Li; Mengjie Duo; Hui Xu; Long Liu; Xiaoxing Su; Xuhua Duan; Peng Luo; Jian Zhang; Zhen Li

doi:10.1016/j.cellsig.2023.110890

Oncogenic pathways refine a new perspective on the classification of hepatocellular carcinoma

Cell Signal. 2023 Nov:111:110890. doi: 10.1016/j.cellsig.2023.110890. Epub 2023 Sep 13.

Authors

Yuyuan Zhang¹, Zaoqu Liu², Jie Li¹, Bailu Wu¹, Xin Li¹, Mengjie Duo³, Hui Xu¹, Long Liu⁴, Xiaoxing Su⁵, Xuhua Duan¹, Peng Luo⁶, Jian Zhang⁶, Zhen Li⁷

Affiliations

¹ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China.
² State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing 100730, China.
³ Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
⁴ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁵ Berry Oncology Corporation, Fujian, China.
⁶ Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
⁷ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China. Electronic address: lzlyct620@163.com.

PMID: 37714446
DOI: 10.1016/j.cellsig.2023.110890

Abstract

Background: Genetic alterations in oncogenic pathways are critical for cancer initiation, development, and treatment resistance. However, studies are limited regarding pathways correlated with prognosis, sorafenib, and transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC).

Methods: In this study, 1928 patients from 11 independent datasets and a clinical in-house cohort were screened to explore the relationships among canonical pathway alterations in HCC patients. The molecular mechanisms, biological functions, immune landscape, and clinical outcomes among three heterogeneous phenotypes were further explored.

Results: We charted the detailed landscape of pathway alterations in the TCGA-LIHC cohort, screened three pivotal pathways (p53, PI3K, and WNT), identified co-occurrence patterns and mutual exclusively, and stratified patients into three altered-pathway dominant phenotypes (ADPs). P53|PI3K ADP characterized by genomic instability (e.g., highest TMB, FGA, FGG, and FGL) indicated an unfavorable prognosis. While, patients in WNT ADP suggested a median prognosis, enhanced immune activation, and sensitivity to PD-L1 therapy. Remarkably, sorafenib and TACE exhibited efficacy for patients in WNT ADP and low frequent alteration phenotype (LFP). Additionally, ADP could work independently of common clinical traits (e.g., AJCC stage) and previous molecular classifications (e.g., iCluster, serum biomarkers).

Conclusions: ADP provides a new perspective for identifying patients at high risk of recurrence and could optimize precision treatment to improve the clinical outcomes in HCC.

Keywords: Co-occurrence; Hepatocellular carcinoma; Molecular phenotype; Oncogenic pathways; Sorafenib; Transcatheter arterial chemoembolization.