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

Background/Aim: 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.

Materials and Methods: 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 (p<0.05) and showing consistent direction of effects were retained, and combined p-values are reported.

Results: 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; p<10⁻⁷). The T allele of rs2238431, a variant located within adenylate cyclase 9 (ADCY9), was associated with poor disease-free survival (hazard ratio=1.73, 95% confidence interval=1.44-2.08; p<10⁻⁸). Both associations remained significant after Bonferroni correction. Functional annotation suggested that the T allele of rs4671908 was associated with increased PLEK expression and overlaps a predicted POU class 5 homeobox 1 (POU5F1)-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 ADCY9.

Conclusion: 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.