Genetic Variants in the p14ARF/MDM2/TP53 Pathway Are Associated with the Prognosis of Esophageal Squamous Cell Carcinoma Patients Treated with Radical Resection

The p14ARF/MDM2/ TP53 pathway is known to play an important role in tumor progression by cell cycle control, although the association between this pathway and the prognosis of esophageal squamous cell carcinoma (ESCC) is unclear. In this study, we explored the association between genetic variants in the p14ARF/MDM2/TP53 pathway and prognosis in ESCC patients with radical resection. 124 ESCC patients with radical resection were included in this retrospective study and genotyped using the MassArray method. According to multivariate Cox hazard analysis and multiple testing, the TC/CC genotype of p14ARF rs3814960 was shown to be strongly related to a decreased overall survival (OS) (HR = 2.77, 95% CI: 1.33–5.75, P = 0.006, Pc = 0.030) and disease-free survival (DFS) (HR = 2.45, 95% CI: 1.30–4.61, P = 0.005, Pc = 0.025). Moreover, patients with the DEL/A +AA genotype of MDM2 rs34886328 had a notably increased OS (HR = 0.27, 95% CI: 0.13–0.56, P = 4.7×10−4, Pc = 0.003) and DFS (HR = 0.22, 95% CI: 0.11–0.43, P = 1.1×10−5, Pc = 6.6×10−5). We also found that these two SNPs had a cumulative effect on the prognosis of ESCC, with the OS (P P p14ARF rs3814960 and/or the DEL/DEL genotype of MDMD2 rs34886328 should have more aggressive treatment and may greatly benefit from early prediction and prevention of an unfavorable prognosis by genotyping before the initiation of therapy. These findings should be further validated in a larger population.已知p14ARF/MDM2/TP53通路可通过调控细胞周期在肿瘤进展中发挥关键作用，但该通路与食管鳞状细胞癌（esophageal squamous cell carcinoma, ESCC）预后的关联尚未明确。本研究旨在探讨p14ARF/MDM2/TP53通路的遗传变异与接受根治性切除术的ESCC患者预后的关联。本回顾性研究纳入124例ESCC根治性切除患者，采用MassArray技术完成基因分型。经多因素Cox风险回归分析及多重检验后发现，p14ARF基因rs3814960位点的TC/CC基因型与总生存期（overall survival, OS）降低显著相关（风险比HR=2.77，95%置信区间95% CI: 1.33–5.75，P=0.006，校正后P值Pc=0.030），同时与无病生存期（disease-free survival, DFS）降低亦呈显著关联（HR=2.45，95% CI: 1.30–4.61，P=0.005，Pc=0.025）。此外，MDM2基因rs34886328位点的DEL/A+AA基因型携带者的OS显著升高（HR=0.27，95% CI: 0.13–0.56，P=4.7×10⁻⁴，Pc=0.003），DFS亦显著提升（HR=0.22，95% CI: 0.11–0.43，P=1.1×10⁻⁵，Pc=6.6×10⁻⁵）。本研究还发现，这两个单核苷酸多态性（single nucleotide polymorphism, SNP）位点对ESCC预后存在累积效应；携带p14ARF rs3814960风险基因型及/或MDM2 rs34886328 DEL/DEL基因型的患者应接受更积极的治疗，并可通过治疗前的基因分型实现不良预后的早期预测与干预，从而获得显著获益。本研究结果尚需在更大规模的人群队列中进一步验证。