Identification of Pyroptosis-related Gene Prognostic Signature in Patients with Hepatocellular Carcinoma

Background: Pyroptosis has been recently identified as a hallmark of cancer biology; however, the potential of pyroptosis-related genes (PRGs) as prognostic markers has not been fully elucidated in hepatocellular carcinoma (HCC). Methods: : 35 PRGs were obtained from the published literature, and pyroptosis subtypes were identified by bioinformatics methods. The risk score model was established applying the LASSO Cox regression method in the TCGA cohort and validated in the ICGC datasets. Additionally, immune infiltration, enriched pathways and genomic alterations were analyzed between high and low risk-score subgroups. Finally, a nomogram containing the pyroptosis risk score and other prognostic related clinical factors was created for predicting the overall survival of HCC. Results: : Based on the expression profile of PRGs, we determined two pyroptosis-related subtypes (cluster A and cluster B) of HCC with different immune characteristics and significantly different prognoses. The risk score model showed that up-regulation of GPX4, CASP8, NOD2, and GSDME was associated with poor prognosis, while NLRP6 was the opposite. Compared with patients with lower risk scores, the high-risk score group had a worse prognosis (P <0.0001) and a higher level of immune cell infiltration. Functional analysis suggested that the highly expressed genes in the high-risk group were mainly concentrated in various signaling pathways, while the low-expressed genes in the high-risk group were mainly enriched in different biochemical metabolic translations. Genomic alterations in high-risk and low-risk populations implied that mutations in the TP53 gene are highly associated with pyroptosis in HCC patients. A nomogram including risk score and TNM stage for 1-year, 3-year, and 5-year overall survival indicated a good prognostic prediction ability. Conclusions: : We developed and verified a prognostic risk model based on PRGs for HCC sufferers, which may provide a robust tool for forecasting prognosis in patients with HCC.