A novel cuproptosis-related prognostic gene signature and validation of differential expression in colon cancer.

[BACKGROUND] Colon cancer is one of the most common gastrointestinal tract tumors and is increasing in incidence worldwide each year. Cuproptosis is a novel cell death pathway that is closely related to energy metabolism. Recent studies suggest that cuproptosis-related genes may play important roles in the progression of colon cancer. Therefore, we aimed to construct prognostic models and column plots for overall survival and progression-free survival of colon cancer by cuproptosis-related genes and search their relationship with immune checkpoints and immune infiltration.

[METHODS] In this study, we systematically analyzed the expression differences, biological functions, and variants of cuproptosis-related genes in colon cancer tissues using the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We analyzed the prognostic characteristics of cuproptosis-related genes in colon cancer using a multifactorial Cox proportional risk regression model and constructed a clinical prognostic model. Subsequently, we analyzed the correlations among cuproptosis-related genes, immune infiltration, and tumor stage.

[RESULTS] Our results revealed that LIPT1, PDHA1, GLS, CDKN2A, FDX1, DLD, and MTF1 were significantly differentially expressed between colon cancer and normal tissues. There was a broad correlation among cuproptosis-related genes, and their mutations were widely present in colon cancer samples. Analysis of cuproptosis-related genes revealed that their roles were primarily related to the tricarboxylic acid cycle and energy metabolism, whereas DLD, PDHB, DLAT, and PDHA1 were the core genes. Using a Cox proportional risk regression model, we revealed the DLAT, LIAS, and CDKN2A genes were associated with the prognosis of colon cancer. We developed a prognostic model based on the overall and progression-free survival of colon cancer, and the area under the curve (AUC) values for the prognostic score for predicting the 5-year overall and progression-free survival were 0.667 and 0.650, respectively. In regard to the survival analysis in terms of overall survival, a higher the risk score based on the cuproptosis-related gene profile resulted in a lower overall survival (HR = 1.67 [1.13–2.48]; log -rank  = 0.011). Progression-free survival was significantly shorter in high-risk patients (HR = 1.36 [0.96–1.93]; log-rank  = 0.084). To improve the clinical utility of the prediction model, we constructed columnar plots of overall survival and progression-free survival with a C-index of 0.810 for overall survival and 0.773 for progression-free survival. Immune infiltration analysis of colon cancer revealed that the expression levels of LIAS, DLAT, and CDKN2A were closely associated with multiple immune cells. Notably, DLAT expression in colon cancer was positively correlated with the expression levels of the immune checkpoint proteins CD274, HAVCR2, and CTLA4, whereas CDKN2A expression was positively correlated with the expression levels of PDCD1, HAVCR2, and CTLA4. We also observed that CDKN2A expression may be associated with colon cancer progression.

[CONCLUSION] Cuproptosis-related genes such as DLAT, LIAS, and CDKN2A possess predictive value in the context of the prognosis and progression of colon cancer, and their relationship with immune checkpoints and immune infiltration may provide a basis for further drug development.