A prognostic signature of cuproptosis and TCA-related genes for hepatocellular carcinoma

Qi Zhang; Longping Ma; Hongyuan Zhou; Yanzhao Zhou; Shuaijing Liu; Qiang Li

doi:10.3389/fonc.2022.1040736

A prognostic signature of cuproptosis and TCA-related genes for hepatocellular carcinoma

Front Oncol. 2022 Oct 17:12:1040736. doi: 10.3389/fonc.2022.1040736. eCollection 2022.

Authors

Qi Zhang¹, Longping Ma¹, Hongyuan Zhou¹, Yanzhao Zhou¹, Shuaijing Liu¹, Qiang Li¹

Affiliation

¹ Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.

Abstract

Background: Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Cuproptosis is a newly defined form of cell death. Copper ion induces cell death by binding to the tricarboxylic acid cycle (TCA). The effect of cuproptosis-related and TCA-related genes on the clinical prognosis of HCC is still unclear. In this study, we explores the genetic changes of cuproptosis-related genes that affect the TCA process and their potential therapeutic value in HCC patients.

Methods: The cuproptosis and TCA-related genes were obtained from cuproptosis-related articles and the molecular signatures database. The prognosis signatures of eight related genes were constructed using the last absolute shrinkage and selection operator (LASSO), and Receiver Operating Characteristic (ROC) curves were used to evaluate the signature. In addition, we analyzed downstream functional enrichment and immune infiltration to explore cuproptosis-inducing drugs and immunotherapeutic responses. All these analyses were validated using multiple datasets of the International Cancer Genome Consortium (ICGC).

Results: TCA and copper malnutrition-related genes (CDKN2A, IDH1, OGDHL, IDH3G, IDH3B, GLS, DLAT, LIPT1) were finally included. According to the risk score, they were divided into high-risk and low-risk groups. Survival analysis showed that the overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. We established a risk prognostic feature to predict the OS of patients with HCC. Based on this feature and the clinical stage, we constructed a nomogram. Functional enrichment analysis revealed pathways related to organelle division and the cell cycle. Different risk scores had different immune abundances in immune cells (including macrophages and regulatory T-cells) and immune pathways (including antigen-presenting cells co-stimulation). Moreover, the drug sensitivity of eleschomol and PD-L1 in the high-risk group was better than that in the low-risk group. The status of TP53 somatic mutation was also closely related to the risk score.

Conclusion: In this study, we established a new prediction signature of eight genes related to cuproptosis and the TCA process, which can effectively predict the prognosis of HCC patients.

Keywords: cuproptosis; elesclomol; hepatocellular carcinoma; overall survival; tricarboxylic acid cycle (TCA cycle).