Genome-wide Analysis Highlights rs4671908 and rs2238431 as Predictors of Survival in Nasopharyngeal Carcinoma

<h3>Background/Aim:</h3> Nasopharyngeal carcinoma (NPC) is more common in certain geographic regions and populations and is frequently diagnosed at advanced stages, highlighting the importance of identifying factors associated with survival. <h3>Materials and Methods:</h3> Patients were selected from two previously conducted genome-wide association studies, resulting in a discovery cohort (n=314) and a validation cohort (n=135). Overall survival and disease-free survival were analyzed using Cox proportional hazards models adjusted for clinical covariates in both cohorts and a combined analysis of the data. Variants associated with survival in both cohorts (<i>p</i>&lt;0.05) and showing consistent direction of effects were retained, and combined <i>p</i>-values are reported. <h3>Results:</h3> The T allele of rs4671908, a variant located upstream of pleckstrin (PLEK) was linked to worse overall survival (hazard ratio=1.85, 95% confidence interval=1.48-2.32; <i>p</i>&lt;10⁻⁷). The T allele of rs2238431, a variant located within adenylate cyclase 9 (<i>ADCY9</i>), was associated with poor disease-free survival (hazard ratio=1.73, 95% confidence interval=1.44-2.08; <i>p</i>&lt;10⁻⁸). Both associations remained significant after Bonferroni correction. Functional annotation suggested that the T allele of rs4671908 was associated with increased <i>PLEK</i> expression and overlaps a predicted POU class 5 homeobox 1 (<i>POU5F1</i>)-binding site. The risky allele was more common in East Asian populations, consistent with the geographic distribution of NPC. The T allele of rs2238431 was associated with reduced expression of <i>ADCY9</i>. <h3>Conclusion:</h3> This study identified rs4671908 and rs2238431 as germline variants associated with survival outcomes in NPC and provides epidemiological evidence that may inform future prognostic stratification of high-incidence populations.