Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Guangxi Medical University, Guangxi Cancer Hospital, Nanning, China.
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.
Mol Carcinog. 2024 Sep;63(9):1712-1721. doi: 10.1002/mc.23767. Epub 2024 Jun 11.
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).
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.
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 (p < 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.
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.
细胞焦亡与多种癌症的进展有关。在肿瘤中引发细胞焦亡会放大免疫反应，从而促进抗肿瘤免疫环境。然而，很少有研究评估细胞焦亡相关基因的功能变异与非口咽头颈部鳞状细胞癌（NON-ORO HNSCC）患者的临床结局之间的关系。
我们对 985 名 NON-ORO HNSCC 患者进行了一项关联研究，这些患者被随机分为两组：发现组 492 名患者和复制组 493 名患者。我们使用 Cox 比例风险回归分析来研究细胞焦亡相关基因的遗传变异与 NON-ORO HNSCC 患者生存之间的关系。贝叶斯虚假发现概率（BFDP）用于多重检验校正。对鉴定出的与生存相关的遗传变异进行功能注释。
在 82 个细胞焦亡相关基因中，有 8254 个单核苷酸多态性（SNP），其中 202 个 SNP 在发现组中通过 BFDP<0.8 的多重检验校正，6 个 SNP 在复制组中保留了统计学意义。在随后的逐步多变量 Cox 回归分析中，两个独立的 SNP（CHMP4A rs1997996 G>A 和 PANX1 rs56175344 C>G）仍然具有统计学意义，调整后的危险比（HR）分别为 1.31（95%置信区间[CI]为 1.09-1.57，p=0.004）和 0.65（95%CI为 0.51-0.83，p=0.0005），用于总生存（OS）。对合并基因型的进一步分析表明，随着不利基因型数量的增加，OS 逐渐恶化（p<0.0001 和 0.021 用于 OS 和疾病特异性生存）。此外，PANX1 rs56175344G 和 CHMP4A rs1997996A 等位基因均与降低的 mRNA 表达水平相关。
细胞焦亡途径基因中的遗传变异可能预测 NON-ORO HNSCC 患者的生存情况，这可能是通过降低基因表达来实现的，但我们的发现需要更大规模的研究来验证。
