Causal Association Between Epidermal Growth Factor and Laryngeal/Oropharyngeal Cancer: A 2-Sample Mendelian Randomization Analysis

The human epidermal growth factor (EGF)-related proteins are thought to play a key role in the pathogenesis of laryngeal cancer (LC) and oropharyngeal cancer (OPC). The aim of this study was to investigate the potential causal relationship between them. A 2-sample Mendelian randomization (MR) analysis utilizing genome-wide association studies (GWAS) data uniquely evaluated causal relationships between EGF-related proteins and both LC and OPC. The core approach utilized IVW, bolstered by weighted median, mode, and MR-Egger estimators for enhanced robustness. Cochran Q, Leave-one-out analysis, and MR-PRESSO were applied to assess heterogeneity, consistency, and pleiotropic effects, ensuring a comprehensive examination. Genetically predicted higher EGF levels were significantly associated with an increased risk of LC (IVW OR=1.492, 95% CI: 1.054–2.111, P =0.024), indicating the role of elevated EGF as a risk factor for LC. No significant causal associations were found between genetically predicted levels of DNER, EGFR, EPS15L1, EGFRvIII, or MEGF10 and the risk of either LC or OPC. Sensitivity analyses showed no strong evidence of horizontal pleiotropy or heterogeneity for the reported associations. This MR study provides genetic evidence supporting a causal relationship between higher circulating EGF levels and increased LC risk. No causal links were established for other investigated EGF pathway proteins or for OPC. These findings highlight EGF as a potential factor in LC etiology, warranting further investigation.