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.
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