Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma.

ABSTRACT

Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.