Comprehensive analysis of metabolic pathway activity subtypes derived prognostic signature in hepatocellular carcinoma

Metabolic reprogramming is one of the hallmarks of cancer, but metabolic pathway activity-related subtypes of hepatocellular carcinoma (HCC) have not been identified.Based on the quantification results of 41 metabolic pathway activities by gene set variation analysis, the training cohort (n = 609, merged by TCGA and GSE14520) was clustered into three subtypes (C1, C2, and C3) with the nonnegative matrix factorization method. Totally 1371 differentially expressed genes among C1, C2, and C3 were identified, and an 8-gene risk score was established by univariable Cox regression analysis, least absolute shrinkage and selection operator method, and multivariable Cox regression analysis.C1 had the strongest metabolic activity, good prognosis, the highest CTNNB1 mutation rate, with massive infiltration of eosinophils and natural killer cells. C2 had the weakest metabolic activity, poor prognosis, was younger, was inclined to vascular invasion and advanced stage, had the highest TP53 mutation rate, exhibited a higher expression level of immune checkpoints, accompanied by massive infiltration of regulatory T cells. C3 had moderate metabolic activity and prognosis, the highest LRP1B mutation rate, and a higher infiltration level of neutrophils and macrophages. Internal cohorts (TCGA, n = 370; GSE14520, n = 239), external cohorts (ICGC, n = 231; GSE116174, n = 64), and clinical subgroup validation showed that the risk score was applicable for patients with diverse clinical features and was effective in predicting the prognosis and malignant progression of patients with HCC. Compared with the low-risk group, the high-risk group had a poor prognosis, enhanced cancer stem cell characteristics, activated DNA damage repair, weakened metabolic activity, cytolytic activity, and interferon response.We identified HCC subtypes from the perspective of metabolism-related pathway activity and proposed a robust prognostic signature for HCC.