Assessing the Impact of Gastroesophageal Reflux Disease on the Risk of Oral Cavity and Pharyngeal Cancer Using Mendelian Randomization

Purpose: Previous observational studies have yielded inconsistent findings regarding the relationship between gastroesophageal reflux disease (GERD) and the risk of oral cavity and pharyngeal cancer (OCPC). This study aims to employ Mendelian randomization (MR) to explore whether a causal relationship exists between GERD and the risk of OCPC and its subtypes. Methods: Using summary data from genome-wide association studies (GWAS), we conducted MR analyses to assess the causal relationship between GERD and OCPC (comprising oral cavity cancer (OCC) and oropharynx cancer (OPC)). We performed univariable MR analyses with GERD as the exposure and OCPC, OCC, and OPC as outcomes. Cigarette smoking, alcohol consumption, body mass index (BMI), and type 2 diabetes (T2D) were adjusted for in the multivariable MR analysis to refine causal estimates. Results: Univariable MR analysis revealed that genetically predicted GERD increased the risk of OCPC (IVW: discovery, OR = 2.09, 95% CI: 1.30-3.37, P = 0.0023; validation, OR = 1.90, 95% CI: 1.26-2.87, P = 0.0020) and OCC (IVW: discovery, OR = 2.01, 95% CI: 1.21-3.33, P = 0.0066; validation: OR = 2.60, 95% CI: 1.47-4.59, P = 0.0010). The association between GERD and OPC was significant only in the discovery analysis (IVW: discovery, OR = 2.30, 95% CI: 1.08-4.89, P = 0.0307; validation: OR = 1.15, 95% CI: 0.67-1.97, P = 0.6199). Multivariable analysis, adjusting for smoking, alcohol, BMI, and T2D, produced consistent results. Conclusions: This MR study indicates a connection between GERD and an overall increased risk of OCPC. The association between GERD and OCC is also significant. This association is independent of CigDay, DrnkWk, BMI, and T2D. However, the link between GERD and OPC is limited and requires further investigation for confirmation. These findings could have significant public health implications and may aid in the prevention and treatment of oral and pharyngeal cancers. Exploring the specific mechanisms behind GERD increasing the risk of OCPC is necessary.