It is controversial whether women have a higher lung cancer susceptibility compared to men. We previously reported higher levels of smoking-related bulky DNA adducts in female lungs. In a pilot study (27 cases), we also found a higher level of female lung cytochrome P4501A1 (CYP1A1) gene expression. In the present extended study we report on the pulmonary expression of several genes involved in polycyclic aromatic hydrocarbon bioactivation in relation to sex, smoking and DNA adducts. CYP1A1, CYP1B1, aryl hydrocarbon receptor and microsomal epoxide hydrolase gene expression was measured by quantitative real-time reverse transcriptase-PCR in 121 normal lung tissue samples. The expression of CYP1A1 and CYP1B1 was significantly higher among current smokers compared to ex-smokers and never-smokers. Among current smokers, females had a 3.9-fold higher median level of CYP1A1 compared to males (p 5 0.011). CYP1B1 expression was not related to sex. Lung DNA adducts (measured by 32 P-postlabeling) were highly significantly related to CYP1A1 (p < 0.0001) irrespective of smoking-status. Our results are consistent with the hypothesis that CYP1A1 plays a significant role in lung DNA adduct formation and support a higher susceptibility to lung cancer among females. ' 2006 Wiley-Liss, Inc.Key words: lung cancer; sex differences; cytochrome P450; DNA adducts Lung cancer ranks first among cancer deaths in the world and tobacco smoke is the major causative agent.1 Although controversial, one of the puzzles in lung carcinogenesis is that women may be at higher risk of smoking associated lung cancer than men. 2-4Two significant, recent epidemiological studies have come to different conclusions. Using base-line CT screening for lung cancer and contrasting women with men, a prevalence-odds ratio of 2.7 was found.5 These data were combined from 2 independent substudies both leading to the same conclusion. From the analysis of data from the Nurses' Health Study of women and the Health Professionals Follow-up Study of men, however, the female to male hazard ratio was only 1.11 (95% CI 0.95-1.31).6 Thus, the question about females as more susceptible to lung cancer remains challenged.Polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene (B[a]P) are present in tobacco smoke, urban air and the working environment, and the B[a]P diol-epoxide metabolite (BPDE) has been established as a lung cancer etiologic agent. There is a strong coincidence of G:C to T:A transversion hotspots in lung cancers at sites of preferential formation of BPDE adducts along the TP53 gene in vitro. 7,8 In the IARC TP53 database, lung G:C to T:A transversions were found to have a higher frequency among female smokers compared to female never-smoker. In contrast, there were no major differences in the mutational spectra of male never-smokers and smokers.9 This may indicate a specific role of tobacco smoke carcinogens (PAH) in generating this particular signature mutation in women.After diffusing into the cell, PAH bind to the aryl hydrocarbon receptor (AHR). Li...

Human lung cancer exhibits a high frequency of transversion mutations at G:C base pairs of the p53 gene, possibly the result of DNA damage by cigarette smoke constituents, most notably benzo[a]pyrene. We have investigated gender differences in the p53 mutational spectrum and levels of hydrophobic DNA adducts. Tumour tissue was obtained from 115 non-small cell lung cancer tumours and examined for mutational alterations in the p53 gene (exons 4-9) using PCR and single-strand conformational polymorphism analysis. We have previously examined exons 5-8 in lung cancer. Sequence analysis of exons 4 and 9 revealed that almost 20% of the mutations were located in exons 4 and 9. The levels of hydrophobic DNA adducts in non-tumorous lung tissue of 55 of the patients were analyzed by the 32P-postlabelling assay. There were both a higher frequency of G:C-->T:A mutations and a higher average hydrophobic DNA adduct level in females than in male patients, even though the level of exposure to carcinogens from cigarette smoking was lower among the females than among the males. Frameshift mutations were more common in women than in men (30 versus 15%). These preliminary findings lend support to epidemiological evidence that women may be at greater risk than men of contracting tobacco-induced lung cancer.

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We have examined DNA restriction fragment length polymorphisms (RFLP) of the Ha-ras-1 gene in DNA from 118 lung cancer patients and 123 unaffected controls. When DNA samples were digested with MspI/HpaII restriction endonucleases. Southern blot analysis demonstrated 4 common, 4 intermediate and 7 different rare alleles in the combined population after hybridization to the pGDa1 probe. Six of the rare alleles were unique for the lung cancer group and 1 rare allele for the control group. The frequency of rare alleles in lung cancer patients (10/236) was significantly different (P less than 0.01) from the control group (1/246). The lung cancer group also had a significantly lower frequency of the common 2.57 kb fragment than the controls (P less than 0.02). The results thus indicate that Ha-ras genotyping may be of value in lung cancer risk assessment.

Taken together, our results indicate that decreased ER expression mediated by DNA methylation may play a role in NSCLC development.