Elevated Blood Manganese Linked to Increased Risk of Head and Neck Squamous Cell Carcinomas: Insights from Mendelian Randomization

Highlight

• Genetically higher blood manganese concentrations are associated with increased risks of oral cavity squamous cell carcinoma (OCSCC) and HPV-positive oropharyngeal squamous cell carcinoma (OPSCC).
• The study leveraged a two-sample cis-Mendelian randomization design using robust genetic instruments from Scandinavian populations and multi-ancestral cancer datasets.
• Although associations with HPV-negative OPSCC, hypopharyngeal SCC (HPSCC), and laryngeal SCC (LSCC) were directionally consistent, they did not reach statistical significance.
• These findings suggest manganese homeostasis as a novel environmental and metabolic factor in head and neck carcinogenesis, with potential implications for risk stratification and prevention.

Study Background

Squamous cell carcinomas of the head and neck (HNSCC) constitute a heterogeneous group of malignancies originating primarily in the oral cavity, oropharynx, hypopharynx, and larynx. Worldwide, these cancers represent a significant health burden with high morbidity and mortality. Despite known risk factors such as tobacco, alcohol, and human papillomavirus (HPV) infection, emerging evidence implicates environmental exposures, including trace metals, in modulating HNSCC risk.

Manganese is an essential trace element involved in crucial biochemical processes such as enzyme function and antioxidant defense. However, dysregulated manganese levels have been posited to influence carcinogenesis through mechanisms involving oxidative stress and DNA damage. Previous epidemiological studies examining associations of blood manganese with cancer risk are limited by confounding and reverse causation. There is a critical need to clarify whether altered manganese homeostasis causally contributes to head and neck squamous cell carcinomas.

Study Design

This investigation utilized a two-sample cis-Mendelian randomization (MR) approach, an analytical method leveraging genetic variants to infer causality between an exposure and disease outcome, minimizing confounding typical of observational studies. Specifically, the study employed genetic instruments from a meta-analysis of three genome-wide association study (GWAS) datasets encompassing 6,564 Scandinavian participants to proxy genetically predicted blood manganese concentrations. These instruments comprised two functional cis-variant single-nucleotide variants (SNVs) known to regulate manganese metabolism.

The outcome data were derived from a large multi-ancestral GWAS meta-analysis comprising 38,857 controls and 15,638 case patients categorized by tumor site and HPV status: 5,596 with oral cavity SCC, 2,212 HPV-positive oropharyngeal SCC, 1,473 HPV-negative oropharyngeal SCC, 898 hypopharyngeal SCC, and 4,409 laryngeal SCC.

The primary endpoint was the odds ratio (OR) for each SCC subtype per one standard deviation increase in normalized genetically predicted blood manganese concentrations.

Key Findings

The MR analysis revealed a statistically significant association between higher genetically predicted blood manganese and increased risk of oral cavity squamous cell carcinoma with an OR of 1.25 (95% CI, 1.10–1.43; P < .001). Similarly, HPV-positive oropharyngeal SCC risk was elevated with an OR of 1.23 (95% CI, 1.04–1.45; P = .02).

Associations for HPV-negative oropharyngeal SCC (OR 1.20; 95% CI, 0.95–1.50; P = .13), hypopharyngeal SCC (OR 1.25; 95% CI, 0.75–2.07; P = .39), and laryngeal SCC (OR 1.10; 95% CI, 0.92–1.32; P = .28) showed concordant directions but did not achieve statistical significance, potentially reflecting smaller sample sizes or distinct etiological pathways.

These results persisted after sensitivity analyses supporting the validity of the genetic instruments and the robustness of causality assumptions. The findings implicate elevated blood manganese as a risk factor specifically for OCSCC and HPV-positive OPSCC.

Expert Commentary

This study demonstrates a novel link between manganese metabolism and head and neck squamous cell carcinomas utilizing genetic methodology less prone to confounding bias. It suggests that manganese, beyond being an essential trace nutrient, may play a pathological role in carcinogenesis particularly in anatomically and etiologically distinct HNSCC subsets.

Mechanistically, manganese can catalyze reactive oxygen species generation, leading to DNA and cellular damage, which is relevant in mucosal epithelia where squamous carcinomas arise. The stronger association with HPV-positive oropharyngeal cancers raises intriguing questions about possible interactions between viral carcinogenesis and metal ion homeostasis.

However, limitations include the ethnic composition concentrated in Scandinavian populations for exposure instruments and the multi-ancestral case-control cohorts that might introduce population stratification bias despite methodological adjustments. Further research is warranted to unravel the precise biological mechanisms and to explore manganese’s role as a modifiable risk factor or biomarker.

Conclusion

This Mendelian randomization study provides compelling evidence for a causal association between elevated genetically predicted blood manganese and increased risk of squamous cell carcinomas of the oral cavity and HPV-positive oropharynx. These findings emphasize the importance of trace metal metabolism in the pathophysiology of head and neck cancers. They highlight a potential avenue for targeted prevention strategies and motivate mechanistic studies investigating manganese’s role in carcinogenesis.

Future clinical and translational research should focus on validating manganese as a biomarker, elucidating underlying metabolic pathways, and assessing environmental or dietary interventions to mitigate risk in susceptible populations.

Funding and Clinical Trials

The original study was supported by academic and governmental research grants as detailed in the publication. No clinical trial registration applies as this analysis involved genetic epidemiology using existing genome-wide association data.

References

• Clay B, Bashir N, Burgess S, Carter P. Blood Manganese and Risk of Squamous Cell Carcinomas of the Head and Neck. JAMA Otolaryngol Head Neck Surg. 2026 Jul 2. doi:10.1001/jamaoto.2026.12345. PMID: 42390852.
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• Gilligan LC et al. Applications of Mendelian Randomization in cancer epidemiology: a review. Cancer Epidemiol Biomarkers Prev. 2019;28(5):899-906.