A novel refined pyroptosis and inflammasome-related genes signature for predicting prognosis and immune microenvironment in pancreatic ductal adenocarcinoma

Pyroptosis is an inflammatory form of cell death, which plays a key role in the development of auto-inflammation and cancer. This study aimed to construct a pyroptosis and inflammasome-related genes for predicting prognosis of the pancreatic ductal adenocarcinoma (PDAC). This study was based primarily on the one-way analysis of variance, univariate Cox regression analysis, Least absolute shrinkage and selection operator (LASSO) Cox regression, a risk-prognostic signature, gene set variation analysis (GSVA), and immune microenvironment analysis, using PDAC data from The Cancer Genome Atlas and International Cancer Genome Consortium databases for the analysis of the role of 676 pyroptosis and inflammasome-related genes in PDAC retrieved from the Reactome and GeneCards databases. Lastly, we collected six paired PDAC and matched normal adjacent tissue samples to verify the expression of signature genes by quantitative real-time PCR (qRT-PCR). We identified 18 candidate pyroptosis and inflammasome-related genes that differed significantly between pathologic grades (stages) of PDAC patients. The univariate Cox and LASSO analyses pointed to six genes as the best variables for constructing a prognostic signature, including ACTA2, C1QTNF9, DNAH8, GATM, LBP, and NGF. The results of the risk prognostic model indicated that the AUCs at 1, 3, and 5 years were greater than 0.62. GSVA revealed that ‘GLYCOLYSIS’, ‘P53 PATHWAY’, ‘KRAS SIGNALING UP’, and ‘INFLAMMATORY RESPONSE’ hallmark gene sets were associated with the risk score. The high-risk group was associated with poor prognosis and was characterized by a lower infiltration of cells involved in anti-tumor immunity; whereas the low-risk group with higher T cells, NK cells, and macrophages showed relatively better survival and significantly higher upregulation of cytolytic scores and inflammation scores. Additionally, crucial pyroptosis and inflammasome-related genes were further validated by qRT-PCR. Our study revealed the prognostic role of the pyroptosis and inflammasome-related genes in PDAC for the first time. Simultaneously, the biological and prognostic heterogeneity of PDAC had been demonstrated, deepening our molecular understanding of this tumor.