Comprehensive Analysis of a Cuproptosis-Related Gene Index in Pancreatic Adenocarcinoma with Significant Implications on Prognosis and Immunotherapy as well as Chemotherapy Efficacy

Abstract Background A novel type of cell death induced by intracellular copper accumulation, principally different from other known ones such as autophagy, ferroptosis, and pyroptosis, was discovered and referred to as “Cuproptosis” recently. As the underlying mechanism was newly identified, its potential connection to pancreatic adenocarcinoma (PAAD) is still an open issue. However, interestingly, one of the 10 Cuproptosis-related genes, CDKN2A, was previously reported as a driver mutation gene in pancreatic adenocarcinoma. Therefore, it raised our interest to develop a Cuproptosis-related gene index (CRGI) for better overall survival (OS) estimation, explore the corresponding relationship with tumor immunology, and discuss the chemotherapy efficacy of commonly used anti-cancerous drugs relevant to CRGI. Methods Gene expression profiles and matched clinical data were curated from publicly accessible sources from which the CRGI was developed. Immunogenic properties were investigated according to the immune checkpoints, potential response to the immunotherapy, cancer immunity cycle, etc. The sensitivity to chemotherapy agents was evaluated through the IC50 curve. The consensus clustering approach was implemented to robustly identify the CRGI-based molecular subtypes and explore the immunotherapy and chemotherapy efficacies. Results A novel gene signature derived from Cuproptosis was established. Compared with those signatures originating from other cell death mechanisms, it exerted a more robust yet more accurate predictive performance. Besides, the result of correlation analysis unraveled the distinct differences in tumor immunology between the high- and low-risk groups. Through in-depth analysis of the IC50 curve of each drug, the predictive chemotherapy efficacy of 32 commonly used anti-cancerous drugs was also found various in high- and low-risk groups. The analysis of molecular subtypes has further confirmed these ideas. Conclusion In the present study, we highlighted the outstanding achievement of CRGI in PAAD prognostic prediction and its association with tumor immunology. These findings may benefit future immunotherapy- and chemotherapy-based interventions.