Development and Validation of a Novel Metabolic-Related Signature Predicting Overall Survival for Pancreatic Cancer

Recently, growing evidence has revealed the significant effect of reprogrammed metabolism on pancreatic cancer in relation to carcinogenesis, progression, and treatment. However, the prognostic value of metabolism-related genes in pancreatic cancer has not been fully revealed. We identified 379 differentially expressed metabolic-related genes (DEMRGs) by comparing 178 pancreatic cancer tissues with 171 normal pancreatic tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression project (GTEx) databases. Then, we used univariate Cox regression analysis together with Lasso regression for constructing a prognostic model consisting of 15 metabolic genes. The unified risk score formula and cutoff value were taken into account to divide patients into two groups: high risk and low risk, with the former exhibiting a worse prognosis compared with the latter. The external validation results of the International Cancer Genome Consortium (IGCC) cohort and the Gene Expression Omnibus (GEO) cohort further confirm the effectiveness of this prognostic model. As shown in the receiver operating characteristic (ROC) curve, the area under curve (AUC) values of the risk score for overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were 0.871, 0.885, and 0.886, respectively. Based on the Gene Set Enrichment Analysis (GSEA), the 15-gene signature can affect some important biological processes and pathways of pancreatic cancer. In addition, the prognostic model was significantly correlated with the tumor immune microenvironment (immune cell infiltration, and immune checkpoint expression, etc.) and clinicopathological features (pathological stage, lymph node, and metastasis, etc.). We also built a nomogram based on three independent prognostic predictors (including individual neoplasm status, lymph node metastasis, and risk score) for the prediction of 1-, 3-, and 5-year OS of pancreatic cancer, which may help to further improve the treatment strategy of pancreatic cancer.