Identification and Validation of Two Heterogeneous Molecular Subtypes and a Prognosis Predictive Model for Hepatocellular Carcinoma Based on Pyroptosis.

ABSTRACT

Hepatocellular carcinoma (HCC) is a worldwide malignant cancer with high incidence and mortality. Considering the high heterogeneity of HCC, clarifying molecular characteristics associated with HCC development could help improve patients' outcomes. Pyroptosis is a novel form of cell death and is noted to be implicated in HCC pathogenesis whereas its molecular feature in HCC is unclear. Thus, we intended to clarify the molecular characteristic as well as the clinical significance of pyroptosis for HCC. A systematic bioinformatics analysis was conducted among 40 pyroptosis-related genes based on The Cancer Genome Atlas, the International Cancer Genome Consortium, and the Gene Expression Omnibus databases. A total of 12 HCC-associated pyroptosis-related genes (HPRGs) were identified to be overexpressed in HCC tissues and significantly connected to patients' poor survival. Through consensus clustering based on the HPRGs' expression, we found patients could be stratified into two distinctive pyroptosis subtypes, PyLow and PyHigh. The PyHigh group owned a notable lower survival rate and a higher high-grade proportion compared with the PyLow subtype. Besides, patients' sensitivities to chemotherapeutic drugs also presented distinctive differences between the two subtypes. Indicated by pathway enrichment analysis and immune characteristic difference analysis, the distinctions between the pyroptosis subtypes may be related to tumor immunity. Further, a five-gene risk model composed of BAK1, CHMP4A, CHMP4B, DHX9, and GSDME was established. Subsequent analyses demonstrated that the model could credibly classify patients as low or high risk and was an independent prognostic indicator for HCC. Abnormal expressions of the five genes were validated by biological experiments and new bioinformatics analysis. In conclusion, this study recognized and verified two heterogeneous pyroptosis subtypes and a predictable prognosis model for HCC. Our work may help facilitate the clinical management and treatment of HCC and understand the functions of pyroptosis in oncology.