A novel cuproptosis-related gene model predicts outcomes and treatment responses in pancreatic adenocarcinoma

Abstract

AbstractBackgroundCuproptosis is recently emerging as a hot spot in cancer research. However, its role in pancreatic adenocarcinoma (PAAD) has not yet been clarified. This study aimed to explore the prognostic and therapeutic implications of cuproptosis-related genes in PAAD.MethodsTwo hundred thirteen PAAD samples from the International Cancer Genome Consortium (ICGC) were split into training and validation sets in the ratio of 7:3. The Cox regression analyses generated a prognostic model using the ICGC cohort for training (n = 152) and validation (n = 61). The model was externally tested on the Gene Expression Omnibus (GEO) (n = 80) and The Cancer Genome Atlas (TCGA) datasets (n = 176). The clinical characteristics, molecular mechanisms, immune landscape, and treatment responses in model-defined subgroups were explored. The expression of an independent prognostic geneTSC22D2was confirmed by public databases, real-time quantitative PCR (RT-qPCR), western blot (WB), and immunohistochemistry (IHC).ResultsA prognostic model was established based on three cuproptosis-related genes (TSC22D2,C6orf136,PRKDC). Patients were stratified into high- and low-risk groups using the risk score based on this model. PAAD patients in the high-risk group had a worse prognosis. The risk score was statistically significantly correlated with most clinicopathological characteristics. The risk score based on this model was an independent predictor of overall survival (OS) (HR = 10.7,p < 0.001), and was utilized to create a scoring nomogram with excellent prognostic value. High-risk patients had a higherTP53mutation rate and a superior response to multiple targeted therapies and chemotherapeutic drugs, but might obtain fewer benefits from immunotherapy. Moreover, elevatedTSC22D2expression was discovered to be an independent prognostic predictor for OS (p < 0.001). Data from public databases and our own experiments showed thatTSC22D2expression was significantly higher in pancreatic cancer tissues/cells compared to normal tissues/cells.ConclusionThis novel model based on cuproptosis-related genes provided a robust biomarker for predicting the prognosis and treatment responses of PAAD. The potential roles and underlying mechanisms ofTSC22D2in PAAD need further explored.