Pan-cancer multi-omics profiling of gasdermins identifies GSDMD as an immune-related prognostic biomarker in kidney renal clear cell carcinoma

Abstract Background The genomic and epigenetic landscape of the gasdermin family across cancers, and its clinical relevance, remain incompletely defined. Methods Multi-omics features of gasdermins across 33 cancer types were analyzed using TCGA data, including RNA-seq, SNV, CNV, DNA methylation, and clinical outcomes. RPPA data were obtained from TCPA, and pharmacogenomic drug response data from GDSC and CTRP. A nomogram for overall survival was developed and externally evaluated in independent KIRC cohorts from GEO (GSE29609), ICGC (RECA-EU), and CPTAC (CPTAC-3-CCRCC). The relationship between GSDMD and immune checkpoint markers was further examined in an exploratory IHC cohort. Results Gasdermin family members showed differential expression across cancers, with expression changes partially concordant with CNV and DNA methylation patterns and associated with prognosis in multiple tumor types. In KIRC, GSDMD stood out with consistently increased mRNA expression accompanied by frequent CNV events and hypomethylation, and these features were associated with unfavorable overall survival and progression-free survival. Higher GSDMD expression was also associated with pathway activity scores and immune-related features in KIRC, including immune infiltration estimates and co-expression patterns of immune checkpoint molecules. Analyses based on public pharmacogenomic resources suggested associations between GSDMD and predicted sensitivity profiles for selected chemotherapeutic and targeted agents. A nomogram integrating GSDMD and immune score showed good prognostic performance, with time-dependent AUCs > 0.75 in external cohorts. In the exploratory IHC cohort (n = 22), GSDMD showed a positive association with CTLA4, a similar trend with LAG3, and an inverse trend with PD-1/PD-L1. Conclusions This integrative analysis supports GSDMD as an immune-related prognostic biomarker candidate in KIRC and provides a framework for further mechanistic and clinical validation.