ASSOCIATIONS OF CYP1A1, GSTM1, AND CYP2E1 POLYMORPHISMS WITH LUNG-CANCER SUGGEST CELL-TYPE SPECIFICITIES TO TOBACCO CARCINOGENS

The dramatic shift in the pathological presentation of lung cancer [th e proportional decrease in squamous cell carcinoma (SCC) and increase in adenocarcinoma (AC)] observed in the United States after the 1950s may have taken place as the result of the reduction in polycyclic arom atic hydrocarbons (PAHs) and the increase in N-nitrosamines in inhaled smoke from filtered low-yield cigarettes, The predominant mutation pa tterns of these tumors also suggest differences in their etiology, We tested the hypothesis that genetic susceptibility to PAHs, as determin ed hy polymorphisms in CYP1A1 and GSTM1, predominantly causes Lung SCC s, and susceptibility to nitrosamines, as determined by polymorphisms in CYP2E1, predominantly causes lung ACs. CYP1A1 and GSTM1 play a majo r role in the metabolic activation and detoxification of PAHs, respect ively, and CYP2E1 plays a major role in the metabolic activation of ni trosamines. We conducted a population-based Ease-control study among 3 41 incident lung cancer cases and 456 controls of Caucasian, Japanese, or Hawaiian origin, In-person interviews collected detailed informati on on Lifestyle risk factors, and DNA extracted from peripheral leukoc ytes was used in PCR-based genotyping assays. Logistic regression anal yses were used to compute odds ratios and 95% confidence intervals (CI s) for each cell type, adjusting for smoking and dietary variables. Th e presence of at Least one copy of the CYP1A1 MspI variant allele vies found to be associated with a 2.4-fold (95% CI, 1.2-4.7) increase in the risk of SCC when this gene was considered singly and a 3.1-fold (9 5% CI, 1.2-7.9) increase in the risk of SCC when combined with a GSTM1 deletion. No significant. association was found between MspI and all lung cancers or other cell types or with the CYP1A1 exon 7 polymorphis m. In contrast, the CYP2E1 RsaI and DraI polymorphisms were not clearl y related to SCC risk, but these homozygous variant genotypes were ass ociated with a 10-fold (95% CI, 0.0-0.5) decrease in the risk of overa ll lung cancer (RsaI variant) and AC (DraI variant) compared to the ho mozygous mild-type genotypes. Inverse associations with these two clos ely linked CYP2E1 polymorphisms were also suggested for small cell car cinoma. In agreement with past experimental and epidemiological data, the associations found in this study between CYP1A1 and lung SCC and b etween CYP2E1 and Lung AC suggest a certain specificity of tobacco smo ke PAHs for lung SCC and tobacco-specific nitrosamines for lung ACs.