What question did this study set out to answer?

This research investigates the clinical relevance of gasdermins, particularly GSDMD, in kidney renal clear cell carcinoma (KIRC).

March 21, 2026Open Access

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

Key Points

This research investigates the clinical relevance of gasdermins, particularly GSDMD, in kidney renal clear cell carcinoma (KIRC).
Analyzed multi-omics features of gasdermins across 33 cancer types using TCGA data.
Developed a nomogram for overall survival using GSDMD and immune scores.
Evaluated GSDMD expression in KIRC cohorts from GEO, ICGC, and CPTAC.
Investigated GSDMD's relationship with immune checkpoint markers using IHC analysis.
GSDMD showed increased mRNA expression linked to worse overall and progression-free survival in KIRC.
Positive associations were found between GSDMD expression and immune checkpoint markers like CTLA4.
The nomogram demonstrated good prognostic performance with AUCs greater than 0.75 in external cohorts.

Abstract

The genomic and epigenetic landscape of the gasdermin family across cancers, and its clinical relevance, remain incompletely defined. 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. 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. This integrative analysis supports GSDMD as an immune-related prognostic biomarker candidate in KIRC and provides a framework for further mechanistic and clinical validation.

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