Metabolism-Related Gene Pairs to Predict the Clinical Outcome and Molecular Characteristics of Early Hepatocellular Carcinoma

Simple Summary After surgery, about 60-70% of early hepatocellular carcinoma patients suffer from relapse within 5 years, hindering long-term survival. Clinical and pathologic features cannot provide an accurate evaluation. We aimed to construct a stratification model from the metabolic aspect to predict the clinical outcome and reveal the molecular characteristics of different prognostic subgroups. An individualized metabolic signature of 10 gene pairs was developed from 250 early HCCs and validated in 311 samples from different datasets. The signature stratified early HCC cases one-by-one into two risk groups with different survival rates. The molecular characteristics of the two risk groups were analyzed by multi-omics data. The relationships with proliferation, immunity, and drug benefits were summarized. The signature was further validated in 47 institutional transcriptomic HCC samples and 101 public proteomic samples. Recurrence is the main factor affecting the prognosis of early hepatocellular carcinoma (HCC), which is not accurately evaluated by clinical indicators. The metabolic heterogeneity of HCC hints at the possibility of constructing a stratification model to predict the clinical outcome. On the basis of the relative expression orderings of 2939 metabolism-related genes, an individualized signature with 10 metabolism-related gene pairs (10-GPS) was developed from 250 early HCC samples in the discovery datasets, which stratified HCC patients into the high- and low-risk subgroups with significantly different survival rates. The 10-GPS was validated in 311 public transcriptomic samples from two independent validation datasets. A nomogram that included the 10-GPS, age, gender, and stage was constructed for eventual clinical evaluation. The low-risk group was characterized by lower proliferation, higher metabolism, increased activated immune microenvironment, and lower TIDE scores, suggesting a better response to immunotherapy. The high-risk group displayed hypomethylation, higher copy number alterations, mutations, and more overexpression of immune-checkpoint genes, which might jointly lead to poor outcomes. The prognostic accuracy of the 10-GPS was further validated in 47 institutional transcriptomic samples and 101 public proteomic samples. In conclusion, the 10-GPS is a robust predictor of the clinical outcome for early HCC patients and could help evaluate prognosis and characterize molecular heterogeneity.