Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer

The short arm of chromosome 3 is thought to harbor a novel oncogenic locus that is important in the genesis of lung cancer, The region at 3p21 is beli eved to contain a distinct locus that is sensitive to loss from the action of tobacco smoke carcinogens and has been reported to be specifically targe ted for deletion in lung cancer. To investigate whether 3p21 alteration in lung cancer is associated with carcinogen exposure, PCR-based analysis was performed to detect loss of heterozygosity (LOH) on chromosome 3 at 3p21 in non-small cell lung carcinoma (NSCLC), We also measured instability at the BAT-26 locus, because the mismatch DNA repair gene, hMLH1, is found at 3p2 1, LOH at 3p21 was analyzed for association with the clinical features of N SCLC, p53 mutation status, polynuclear aromatic hydrocarbon-DNA adduct leve ls (measured using P-32-postlabeling) and carcinogen exposure information i ncluding cigarette smoking and asbestos exposure, Of 219 lung cancers, 150 cases (68.5%) were informative at the D3S1478 locus, and 44.2% of squamous cell carcinoma cases and 30.2% of adenocarcinoma cases showed 3p21 LOH, Non e of the cancers showed BAT-26 instability, The prevalence of 3p21 LOH was higher in both current and former smokers compared with never smokers and w as higher in p53 mutated cases. Among squamous cell carcinoma cases, there was a strong association of increased 3p21 LOH with increasing polynuclear aromatic hydrocarbon-DNA adducts levels (P = 0.03), as well as an increased prevalence LOH with earlier age of smoking initiation (P = 0.02), Our resu lts confirm that 3p21 LOH is strongly associated with measures of biologica lly effective dose of exposure to tobacco carcinogens, Our results also sug gest that alterations of hMLH1 are not related to any of the reported assoc iations, because there was no evidence of microsatellite instability. Final ly, LOH in 3p21 may be an early molecular event in NSCLC, because it is sig nificantly associated with a tendency to start smoking at a young age.