PANoptosis-based molecular subtyping and HPAN-index predicts therapeutic response and survival in hepatocellular carcinoma

Fei Song; Cheng-Gui Wang; Jia-Zhen Mao; Tian-Lun Wang; Xiao-Liang Liang; Chen-Wei Hu; Yu Zhang; Lu Han; Zhong Chen

doi:10.3389/fimmu.2023.1197152

PANoptosis-based molecular subtyping and HPAN-index predicts therapeutic response and survival in hepatocellular carcinoma

Front Immunol. 2023 Jun 15:14:1197152. doi: 10.3389/fimmu.2023.1197152. eCollection 2023.

Authors

Fei Song¹, Cheng-Gui Wang¹, Jia-Zhen Mao¹, Tian-Lun Wang¹, Xiao-Liang Liang¹, Chen-Wei Hu¹, Yu Zhang¹, Lu Han², Zhong Chen¹

Affiliations

¹ Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
² Jiangsu Vocational College of Medicine, Yancheng, China.

Abstract

Background: Hepatocellular carcinoma (HCC) is a highly prevalent and fatal cancer. The role of PANoptosis, a novel form of programmed cell death, in HCC is yet to be fully understood. This study focuses on identifying and analyzing PANoptosis-associated differentially expressed genes in HCC (HPAN_DEGs), aiming to enhance our understanding of HCC pathogenesis and potential treatment strategies.

Methods: We analyzed HCC differentially expressed genes from TCGA and IGCG databases and mapped them to the PANoptosis gene set, identifying 69 HPAN_DEGs. These genes underwent enrichment analyses, and consensus clustering analysis was used to determine three distinct HCC subgroups based on their expression profiles. The immune characteristics and mutation landscape of these subgroups were evaluated, and drug sensitivity was predicted using the HPAN-index and relevant databases.

Results: The HPAN_DEGs were mainly enriched in pathways associated with the cell cycle, DNA damage, Drug metabolism, Cytokines, and Immune receptors. We identified three HCC subtypes (Cluster_1, SFN+PDK4-; Cluster_2, SFN-PDK4+; Cluster_3, SFN/PDK4 intermediate expression) based on the expression profiles of the 69 HPAN_DEGs. These subtypes exhibited distinct clinical outcomes, immune characteristics, and mutation landscapes. The HPAN-index, generated by machine learning using the expression levels of 69 HPAN_DEGs, was identified as an independent prognostic factor for HCC. Moreover, the high HPAN-index group exhibited a high response to immunotherapy, while the low HPAN-index group showed sensitivity to small molecule targeted drugs. Notably, we observed that the YWHAB gene plays a significant role in Sorafenib resistance.

Conclusion: This study identified 69 HPAN_DEGs crucial to tumor growth, immune infiltration, and drug resistance in HCC. Additionally, we discovered three distinct HCC subtypes and constructed an HPAN-index to predict immunotherapeutic response and drug sensitivity. Our findings underscore the role of YWHAB in Sorafenib resistance, presenting valuable insights for personalized therapeutic strategy development in HCC.

Keywords: PANoptosis; YWHAB; drug sensitivity; hepatocellular carcinoma (HCC); immune characteristics; prognostic index.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / therapy
Cell Cycle
Humans
Liver Neoplasms* / genetics
Liver Neoplasms* / therapy
Sorafenib

Substances

Sorafenib

Grants and funding

This study was supported by the National Natural Science Foundation of China grants (81871927, 81070360), 2021 Changchun University of Chinese Medicine School-level Clinical Practice Teaching Reform Special Research Project (XJLCSJ202146), and the Nantong Hepatobiliary and Pancreatic Surgery Disease Research Center Construction Project (HS2015001).