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Mutations in theCHEK2gene have been associated with increased risks of breast, prostate and colon cancer. In contrast, a previous report suggests that individuals with the I157T missense variant of theCHEK2gene might be at decreased risk of lung cancer and upper aero-digestive cancers. To confirm this hypothesis, we genotyped 895 cases of lung cancer, 430 cases of laryngeal cancer and 6391 controls from Poland for four founder alleles in theCHEK2gene, each of which has been associated with an increased risk of cancer at several sites. The presence of aCHEK2mutation was protective against both lung cancer [odds ratio (OR) = 0.3; 95% confidence interval (CI) 0.2–0.5;P= 3 × 10−8] and laryngeal cancer (OR = 0.6; 95% CI 0.3–0.99;P= 0.05). The basis of the protective effect is unknown, but may relate to the reduced viability of lung cancer cells with aCHEK2mutation. Lung cancers frequently possess other defects in genes in the DNA damage response pathway (e.g.p53mutations) and have a high level of genotoxic DNA damage induced by tobacco smoke. We speculate that lung cancer cells with impairedCHEK2function undergo increased rates of cell death.

Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers