DESCRIPTION: The proposed study builds upon the existing recruitment of
study subjects and procurement of epidemiologic data and blood samples from
two ongoing studies of lung cancer, led by Drs. Margaret Spitz and Waun Ki
Hong. The application proposes to validate the findings of a preliminary
case-control study which revealed that the level of in vitro benzo[a]pyrene
diol epoxide (BPDE)-induced DNA adducts was significantly associated with
the risk of lung cancer. The rationale for developing this biomarker is not
given the same in-vitro exposure to smoking-related carcinogens, cells from
some individuals did not remove carcinogen-induced adducts sufficiently,
indicating an increased risk of developing smoking-related cancer. The
study will evaluate the usefulness of this new in vitro-induced DNA adduct
assay and identify individuals who may be susceptible to smoking-related
cancers. Using the study protocol, personnel, and data-collection
instruments currently in operation, the preliminary study of 21 cases and 41
controls to a case-control will be expanded to a study of 250 lung-cancer
cases and 250 healthy controls (matched by age, sex ethnicity and smoking
status). The application outlines the following Specific Aims: 1) to
determine the association between the levels of in vitro-induced carcinogen
adducts and risk of lung cancer; 2) to determine the correlation between
levels of BPE-induced adducts and DNA repair capacity; and 3) to determine
the association of the levels of BPE-induced DNA adducts with other related
susceptibility factors and biomarkers for lung-cancer risk. The level of
DNA adducts induced by in vitro by an ultimate carcinogen (BPDE) largely
reflects the level of overall genomic repair capacity of the whole cells
plus cellular detoxification. It is hypothesized that the in vitro-induced
adducts associated with lung cancer susceptibility will substantiate the
predictive role of this new BPDE-induced DNA adduct assay in identifying
subgroups of smokers at particularly high risk for developing lung cancer
and further elucidate the mechanisms of tobacco carcinogenesis. Such
high-risk individuals would be targetted for intensive smoking cessation
interventions, could be enrolled in chemoprevention trials and might be
suitable for screening programs, not appropriate for the general population.
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