Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant-463A of the myeloperoxidase gene

Myeloperoxidase (MPO), an enzyme that is highly expressed in neutrophil leu kocytes, transforms precarcinogens such as benzo(a)pyrene and aromatic amin es to highly reactive intermediates. A G/A polymorphism located 463 bp upst ream of exon 1 in the promoter region strongly reduces MPO mRNA expression. In a matched case-control study, 196 lung cancer, 245 laryngeal cancer, an d 255 pharyngeal cancer patients from the Berlin area were investigated for frequency of the G-463A polymorphism by PCR/RFLP, using AciI, They were ma tched by age and gender to hospital patients without known malignancies, Mo reover, 270 healthy volunteers were genotyped, obtaining 61.1% of individua ls 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 significantl y less frequent. Crude odds ratios for carriers of one or two A alleles, co mpared to wild-type G/G, mere 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% Ct, 0.57-1.17; P = 0.27) for p haryngeal cancer patients. The relative risks, adjusted for age, gender, an d extent of cigarette smoking were 0.47 (95% CI, 0.28-0.79; P = 0.004), 0.6 6 (95% CI, 0.44-1.01; P = 0.054), and 0.75 (95% CI, 0.51-1.12; P = 0.16) fo r lung, larynx, and pharyngeal cancer, respectively. Strikingly, relative r isk 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 c ancer, and one reference subject displayed novel G/A mutations at -297 nucl eotide and -296 nucleotide, destroying a constitutive AciI cleavage site. O ur data finally suggest that the MPO -463A variant is a protective factor i n the etiology of lung and larynx cancer, but possibly not of pharyngeal ca ncer.