A systematic pan-cancer analysis of the gasdermin (GSDM) family of genes and their correlation with prognosis, the tumor microenvironment, and drug sensitivity

Abstract

Background: Pyroptosis is a programmed cell death process mediated by the gasdermin (GSDM) protein. However, limited research has been conducted to comprehensively analyze the contribution of the GSDM family in a pan-cancer setting. Methods: We systematically evaluated the gene expression, genetic variations, and prognostic values of the GSDM family members. Furthermore, we investigated the association between the expression of GSDM genes and immune subtypes, the tumor microenvironment (TME), the stemness index, and cancer drug sensitivities by means of a pan-cancer analysis. Results: GSDM genes were highly upregulated in most of the tested cancers. Low-level mutation frequencies within GSDM genes were common across the examined types of cancer, and their expression levels were associated with prognosis, clinical characteristics, TME features, and stemness scores in several cancer types, particularly those of the urinary system. Importantly, we found that the expressions of GSDMB, GSDMC, and GSDMD were higher in kidney carcinomas, and specifically kidney renal clear cell carcinoma (KIRC); which adversely impacted the patient outcome. We showed that GSDMD was potentially the most useful biomarker for KIRC. The drug sensitivity analysis demonstrated that the expressions of GSDM genes were correlated with the sensitivity of tumor cells to treatment with chemotherapy drugs nelarabine, fluphenazine, dexrazoxane, bortezomib, midostaurin, and vincristine. Conclusion: GSDM genes were associated with tumor behaviors and may participate in carcinogenesis. The results of this study may therefore provide new directions for further investigating the role of GSDM genes as therapeutic targets in a pan-cancer setting.

Keywords: GSDM family; drug sensitivity; prognosis; pyroptosis; tumor microenvironment.

FIGURE 1

Comparison of the GSDM gene expression landscape in different cancers and corresponding normal tissues. (A) Differences in GSDM gene expression in the pan-cancer setting (B). GSDM family gene expression levels in different cancer types (TCGA data); red, high gene expression; green, low gene expression. (C–H) Differences in GSDM mRNA levels between normal and cancer tissues. An adjusted cutoff value of p < 0.05 denotes statistically significant differences. The asterisks represent statistical significance with adjusted p value (*p < 0.05, **p < 0.01, ***p < 0.001). GSDM, gasdermin; TCGA, The Cancer Genome Atlas.

FIGURE 2

Genetic changes and TME features associated with GSDM genes in the pan-cancer setting. (A) Mutation spectrum of the GSDM genes in the pan-cancer setting (B) Correlation of GSDM gene expression with TMB and MSI in various cancer types (TCGA data). An adjusted cutoff value of p < 0.05 denotes statistically significant differences (*p < 0.05, **p < 0.01, ***p < 0.001). TME, tumor microenvironment; TMB, tumor mutational burden; MSI, microsatellite instability. GSDM, gasdermin.

FIGURE 3

Association between GSDM gene expression and different immune subtypes and clinical traits in the pan-cancer setting. (A) Differences in GSDM gene expressions in six pan-cancer immune subtypes: C1 (Wound Healing), C2 (IFN-γ Dominant), C3 (Inflammatory), C4 (Lymphocyte Depleted), C5 (Immunologically Quiet), and C6 (TGF-β Dominant). (B–G) Correlation between the tumor stage and GSDM gene expression. An adjusted cutoff value of p < 0.05 denotes statistically significant differences (*p < 0.05, **p < 0.01, ***p < 0.001). GSDM, gasdermin; IFN-γ, interferon gamma; TGF-β, transforming growth factor-beta.

FIGURE 4

Survival analysis in relation to GSDM gene expression in the pan-cancer setting (TCGA data). (A–N) Kaplan-Meier survival curves for the high and low GSDM gene expression groups in the different cancers (TCGA data). (O) Cox regression analysis of GSDM gene expression and tumor survival in different cancer types (TCGA data). A hazard ratio <1 and >1 denotes low and high risk, respectively. GSDM, gasdermin; TCGA, The Cancer Genome Atlas.

FIGURE 5

Survival analysis in relation to the expression of GSDM genes in the pan-cancer setting (Kaplan-Meier plotter database). Solid color represents log-rank p-value; higher color intensity indicates greater statistical significance. A cutoff value of p < 0.05 denotes statistically significant differences. GSDM, gasdermin.

FIGURE 6

The prognostic performance of GSDM genes. Receiver operating characteristic (ROC) curve showing the prognostic performances of GSDM genes in KIRC using data from TCGA (A) and TARGET (B) databases. GSDM, gasdermin; KIRC, kidney renal clear cell carcinoma; TARGET, therapeutically applicable research to generate effective treatments; TCGA, The Cancer Genome Atlas.

FIGURE 7

Correlation analysis of GSDM gene expression and the TME and stemness score in the pan-cancer setting. (A–D) Association between GSDM gene expression and the immune score (A), the RNA stemness score (B), the DNA stemness score (C), and tumor purity (D) in the different cancers; red represents a positive correlation, and blue represents a negative correlation. An adjusted cutoff value of p < 0.05 denotes statistically significant differences (*p < 0.05, **p < 0.01, ***p < 0.001). GSDM, gasdermin; TME, tumor microenvironment.

FIGURE 8

Drug sensitivity analysis of GSDM genes in the pan-cancer setting. GSDM, gasdermin.