Increased Blood Manganese Raises Risk for Some Head and Neck Cancers

Previous epidemiologic studies have shown that increased levels of trace metals, such as manganese, in the blood are associated with a higher risk for development of oral cancer. Because these studies were subject to a number of limiting biases, Benjamin Clay, MBBChir, and colleagues conducted a new two-sample cis-mendelian randomization study to determine whether a person’s genetic predisposition for an increased level of manganese in the blood is associated with risk for squamous cell carcinomas of the oral cavity (OCSCC), oropharynx (OPSCC), hypopharynx (HPSCC), and larynx (LSCC).

 In the study, which was published in the JAMA Otolaryngology–Head & Neck Surgery, investigators pooled data from 6,564 Scandinavian participants and identified gene variants that reliably predicted a person’s blood manganese levels. The source of the data was a meta-analysis of three individual-level genome-wide association study datasets.

They also gathered data separately from 38,857 control  participants and from 5,596 case patients with OCSCC, 2,212 case patients with human papillomavirus (HPV)–positive OPSCC, 1,473 case patients with HPV-negative OPSCC, 898 case patients with HPSCC, and 4,409 case patients with LSCC.

They assessed whether the same gene variants that raised manganese levels in the Scandinavian population showed up more often in patients with cancer compared with control  participants. The risk for developing these five cancers was measured as an odds ratio (OR) for each increase of 1 standard deviation in blood manganese.

 They found that elevated blood manganese was associated with higher risk for OCSCC (OR, 1.25; 95% CI, 1.10-1.43; P<0.001) and HPV-positive OPSCC (OR, 1.23; 95% CI, 1.04-1.45; P=0.02). Both associations were statistically significant.

HPV-negative OPSCC was also associated with higher manganese levels, but the association was not significant (OR, 1.20; 95% CI, 0.95-1.50; P=0.13). The same held true for HPSCC (OR, 1.25; 95% CI, 0.75-2.07; P=0.39) and LSCC (OR, 1.10; 95% CI, 0.92-1.32; P=0.28)

 The link between oral cancer and higher manganese levels was most obvious with OCSCC and HPV-positive OPSCC; the other three cancers showed a nonsignificant association. The findings from this study raise important questions about the specific mechanism by which manganese raises the risk for head and neck cancer. The study authors indicate that future research should be done to determine the underlying pathophysiologic mechanisms of the association with the goal of developing strategies for prevention of such cancers.