Effect of Blood Manganese on the Risk of Squamous Cell Carcinomas of the Head and Neck

Importance Squamous cell carcinomas of the oral cavity (OCSCC), oropharynx (OPSCC), hypopharynx (HPSCC), and larynx (LSCC) are the most common forms of head and neck cancer globally. Epidemiological studies have identified variations in blood trace metal concentrations as potential risk factors for the development of these cancers, but these studies are susceptible to multiple biases. Objective We aimed to determine if variations in genetically predicted blood manganese are associated with risk of OCSCC, OPSCC, HPSCC and LSCC. Design Two-sample cis-Mendelian randomisation study Setting Population-based Participants Genetic associations for blood manganese concentration were obtained from a meta-analysis of three individual-level genome-wide association study (GWAS) datasets of 6564 Scandinavian participants. Genetic associations for the development of the specified cancers were obtained from a non-overlapping cross-ancestral meta-analysis of 23 GWAS datasets, including 38,857 healthy controls, 5,596 OCSCC cases, 2,212 HPV-positive OPSCC cases, 1,473 HPV-negative OPSCC cases, 898 HPSCC cases, and 4,409 LSCC cases. Exposure(s) Increases in genetically predicted whole blood manganese concentration proxied by a genetic instrument including two cis-variants (single nucleotide polymorphisms) selected due to their known functions in regulating manganese metabolism. Main Outcome(s) and Measure(s) The primary outcome was the odds ratio (95% confidence interval) for risk of OCSCC, OPSCC (HPV-positive and HPV-negative), HPSCC and LSCC, per standard deviation increase in whole blood manganese concentration after rank-based inverse normalisation transformation. Results Genetically predicted higher blood manganese was found to be significantly associated with increased risk of OCSCC (OR = 1.25 95% CI 1.10 to 1.43) and HPV-positive OPSCC (OR = 1.23, 95% CI 1.04 to 1.45). Associations between blood manganese and HPV-negative OPSCC (OR = 1.20, 95% CI 0.95 to 1.50), HPSCC (OR = 1.25, 95% CI 0.75 to 2.07), and LSCC (OR = 1.10, 95% CI 0.92 to 1.32) were directionally concordant but non-significant. Conclusion and Relevance We demonstrate significant associations between higher blood manganese concentrations and risk of OCSCC and HPV-positive OPSCC. Further work should aim to establish the pathophysiological mechanisms underlying this association to inform potential public health strategies for the prevention of these cancers.