Abstract
Introduction: Reliable biomarkers are in need to predict the prognosis of hepatocellular carcinoma (HCC). Whilst recent evidence has established the critical role of copper homeostasis in tumor growth and progression, no previous studies have dealt with the copper-related genes (CRGs) signature with prognostic potential in HCC. Methods: To develop and validate a CRGs prognostic signature for HCC, we retrospectively included 353 and 142 patients as the development and validation cohort, respectively. Copper-related Prognostic Signature (Copper-PSHC) was developed using differentially expressed CRGs with prognostic value. The hazard ratio (HR) and the area under the time-dependent receiver operating characteristic curve (AUC) during 3-year follow-up were utilized to evaluate the performance. Additionally, the Copper-PSHC was combined with age, sex, and cancer stage to construct a Copper-clinical-related Prognostic Signature (Copper-CPSHC), by multivariate Cox regression. We further explored the underlying mechanism of Copper-PSHC by analyzing the somatic mutation, functional enrichment, and tumor microenvironment. Potential drugs for the high-risk group were screened. Results: The Copper-PSHC was constructed with nine CRGs. Patients in the high-risk group demonstrated a significantly reduced overall survival (OS) (adjusted HR, 2.65 [95% CI, 1.83-3.84] and 3.30, [95% CI, 1.27-8.60] in the development and validation cohort, respectively). The Copper-PSHC achieved a 3-year AUC of 0.74 [95% CI, 0.67-0.82] and 0.71 [95% CI, 0.56-0.86] for OS in the development and validation cohort, respectively. Copper-CPSHC yield a 3-year AUC of 0.73 [95% CI, 0.66-0.80] and 0.72 [95% CI, 0.56-0.87] for OS in the development and validation cohort, respectively. Higher tumor mutation burden, downregulated metabolic processes, hypoxia status and infiltrated stroma cells were found for the high-risk group. Six small molecular drugs were screened for the treatment of the high-risk group. Conclusion: Copper-PSHC services as a promising tool to identify HCC with poor prognosis and to improve disease outcomes by providing potential clinical decision support in treatment.