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Substantially Reduced Risk of Cancer of the Aerodigestive Tract in Subjects with Variant -463A of the Myeloperoxidase Gene¹

Institute of Clinical Pharmacology [I. C., J. B., J. G., C. M., I. R.], Department of Oto-Rhino-Laryngology [S. H.], and Department of Surgery [J. M. M.], University Medical Center Charité, Humboldt University of Berlin, 10098 Berlin, Germany, and Department of Pneumology, Lungenklinik Heckeshorn, 14109 Berlin, Germany [R. L.]

Myeloperoxidase (MPO), an enzyme that is highly expressed in neutrophil leukocytes, transforms precarcinogens such as benzo(a)pyrene and aromatic amines to highly reactive intermediates. A G/A polymorphism located 463 bp upstream of exon 1 in the promoter region strongly reduces MPO mRNA expression. In a matched case-control study, 196 lung cancer, 245 laryngeal cancer, and 255 pharyngeal cancer patients from the Berlin area were investigated for frequency of the G-463A polymorphism by PCR/RFLP, using AciI. They were matched by age and gender to hospital patients without known malignancies. Moreover, 270 healthy volunteers were genotyped, obtaining 61.1% of individuals with MPO genotype -463G/G, 34.8% of individuals with genotype G/A, and 4.1% of individuals with genotype A/A. In lung and laryngeal cancer patients, but not in pharyngeal cancer patients, mutant genotypes were significantly less frequent. Crude odds ratios for carriers of one or two A alleles, compared to wild-type G/G, were 0.58 [95% confidence interval (CI), 0.38–0.88; P = 0.011] for lung cancer patients, 0.63 (95% CI, 0.43–0.92; P = 0.017) for laryngeal cancer patients, and 0.82 (95% CI, 0.57–1.17; P = 0.27) for pharyngeal cancer patients. The relative risks, adjusted for age, gender, and extent of cigarette smoking were 0.47 (95% CI, 0.28–0.79; P = 0.004), 0.66 (95% CI, 0.44–1.01; P = 0.054), and 0.75 (95% CI, 0.51–1.12; P = 0.16) for lung, larynx, and pharyngeal cancer, respectively. Strikingly, relative risk for carriers of -463A among adenocarcinoma of the lung was 0.24 (95% CI, 0.10–0.58; P = 0.002). Two cases with larynx cancer, one case with lung cancer, and one reference subject displayed novel G/A mutations at -297 nucleotide and -296 nucleotide, destroying a constitutive AciI cleavage site. Our data finally suggest that the MPO -463A variant is a protective factor in the etiology of lung and larynx cancer, but possibly not of pharyngeal cancer.

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