The fact that only about 15 percent of smokers will develop lung cancer in their lifetime suggests a genetic susceptibility to tobacco-related cancers. This inherited variation in susceptibility may be partly due to genetically determined variation in DNA repair capacity that influences the rate of DNA damage removal and fixation of mutations. While mutations occurring in genes involved in signal transduction, regulation of gene expression, and cellular proliferation may be responsible for tumor initiation, genetic changes in DNA repair genes may be even earlier events in tumorigenesis. The well-studied smoking- related carcinogen benzo[a]pyrene induces damage to cellular DNA primarily through adducts formed by its metabolite, benzo[a]pyrene diol epoxide (BPDE), an ultimate carcinogen. These DNA adducts are repaired by a nucleotide-excision repair (NER) pathway that is responsible for the restoration of normal DNA structure. It is conceivable that baseline level of transcript of DNA repair gene reflects cellular ability to meet repair demand once the cells are stimulated by carcinogen exposure. Although reduced DNA repair capacity has been shown to be associated with smoking-related cancer such as lung cancer, few studies have been conducted to evaluate the role of expression of DNA repair genes in the etiology of lung cancer. We hypothesize that genetically determined alteration in the baseline expression of genes involved in NER is associated with risk of lung cancer. In this pilot study, we propose to test our hypothesis in a pilot study of 75 cases with lung cancer and 75 controls without cancer. We will determine differences of the relative expression levels of five NER genes (ERCC1, ERCC3, ERCC5, ERCC6 and XPC) in phytohemagglutinin-stimulated peripheral lymphocytes of patients with lung cancer and controls without cancer. We will also determine the association between the relative expression levels of NER genes and the risk of lung cancer with adjustment for other known epidemiologic risk factors, which may have an effect on the baseline expression. The results of this pilot study may help validate the usefulness of this new RT-PCR assay in large scale epidemiologic studies in the future.
