Abstract
BACKGROUND: There is growing evidence that pseudogenes may serve as prognostic biomarkers in several cancers. The present study was designed to develop and validate an accurate and robust pseudogene pairs-based signature for the prognosis of hepatocellular carcinoma (HCC). METHODS: RNA-sequencing data from 374 HCC patients with clinical follow-up information were obtained from the Cancer Genome Atlas (TCGA) database and used in this study. Survival-related pseudogene pairs were identified, and a signature model was constructed by Cox regression analysis (univariate and least absolute shrinkage and selection operator). All individuals were classified into high- and low-risk groups based on the optimal cutoff. Subgroups analysis of the novel signature was conducted and validated in an independent cohort. Pearson correlation analyses were carried out between the included pseudogenes and the protein-coding genes based on their expression levels. Enrichment analysis was performed to predict the possible role of the pseudogenes identified in the signature. RESULTS: A 19-pseudogene pair signature, which included 21 pseudogenes, was established. Patients in high-risk group demonstrated an increased the risk of adverse prognosis in the TCGA cohort and the external cohort (all P < 0.001). The novel pseudogene signature was independent of other conventional clinical variables used for survival prediction in HCC patients in the two cohorts revealed by the multivariate Cox regression analysis (all P < 0.001). Subgroup analysis further demonstrated the diagnostic value of the signature across different stages, grades, sexes, and age groups. The C-index of the prognostic signature was 0.761, which was not only higher than that of several previous risk models but was also much higher than that of a single age, sex, grade, and stage risk model. Furthermore, functional analysis revealed that the potential biological mechanisms mediated by these pseudogenes are primarily involved in cytokine receptor activity, T cell receptor signaling, chemokine signaling, NF-κB signaling, PD-L1 expression, and the PD-1 checkpoint pathway in cancer. CONCLUSION: The novel proposed and validated pseudogene pair-based signature may serve as a valuable independent prognostic predictor for predicting survival of patients with HCC.