Comparative analysis identifies genetic and molecular factors associated with prognostic clusters of PANoptosis in glioma, kidney and melanoma cancer.

The importance of inflammatory cell death, PANoptosis, in cancer is increasingly being recognized. PANoptosis can promote or inhibit tumorigenesis in context-dependent manners, and a computational approach leveraging transcriptomic profiling of genes involved in PANoptosis has shown that patients can be stratified into PANoptosis High and PANoptosis Low clusters that have significant differences in overall survival for low grade glioma (LGG), kidney renal cell carcinoma (KIRC) and skin cutaneous melanoma (SKCM). However, the molecular mechanisms that contribute to differential prognosis between PANoptosis clusters require further elucidation. Therefore, we performed a comprehensive comparison of genetic, genomic, tumor microenvironment, and pathway characteristics between the PANoptosis High and PANoptosis Low clusters to determine the relevance of each component in driving the differential associations with prognosis for LGG, KIRC and SKCM. Across these cancer types, we found that activation of the proliferation pathway was significantly different between PANoptosis High and Low clusters. In LGG and SKCM, we also found that aneuploidy and immune cell densities and activations contributed to differences in PANoptosis clusters. In individual cancers, we identified important roles for barrier gene pathway activation (in SKCM) and the somatic mutation profiles of driver oncogenes as well as hedgehog signaling pathway activation (in LGG). By identifying these genetic and molecular factors, we can possibly improve the prognosis for at risk-stratified patient populations based on the PANoptosis phenotype in LGG, KIRC and SKCM. This not only advances our mechanistic understanding of cancer but will allow for the selection of optimal treatment strategies.