Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma.

ABSTRACT

BACKGROUND: Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC). METHODS: We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants. RESULTS: There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (ptrend < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels. CONCLUSIONS: Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.