Development and validation of a robust immune-related risk signature for hepatocellular carcinoma

Increasing evidence has indicated immune-related genes (IRGs) play a key role in the development of hepatocellular carcinoma (HCC). Whereas, there have been no investigations proposing a reliable prognostic signature in terms of IRGs. This study aimed to develop a robust signature based on IRGs in HCC. A total of 597 HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases were enrolled in this study.

The TCGA cohort was utilized for discovery, and the ICGC cohort was utilized for validation. Multiple algorithms were implemented to identify key prognostic IRGs and establish an immune-related risk signature. Bioinformatics analysis and R soft tools were utilized to annotate underlying biological functions.

A total of 1416 differentially expressed mRNAs (DEMs) were screened, of which 90 were differentially expressed IRGs (DEIRGs). Using univariate Cox regression analysis, we identified 33 prognostically relevant DEIRGs. Using least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis, we extracted 8 optimal DEIRGs to construct a risk signature in the TCGA cohort, and the signature was verified in the ICGC cohort. We also built a nomogram to increase the accuracy of predicting HCC prognosis. By investigating the relationship of the risk score and 8 risk genes from our signature with clinical traits, we found that the aberrant expression of the immune-related risk genes is correlated with the development of HCC. Moreover, the high-risk group was higher than the low-risk group in terms of tumor mutation burden (TMB), immune cell infiltration, and the expression of immune checkpoints (programmed cell death protein 1 [PD-1], programmed cell death ligand 1 [PD-L1], and cytotoxic T-lymphocyte-related protein 4 [CTLA-4]), and functional enrichment analysis indicated the signature enriched an intensive immune phenotype.

This study developed a robust immune-related risk signature and built a predictive nomogram that reliably predict overall survival in HCC, which may be helpful for clinical management and personalized immunotherapy decisions.