DESCRIPTION (provided by applicant):
This proposal's specific objective is to evaluate the validity of using gene
expression in buccal cells to accurately reflect gene expression in human lung
when both are tobacco smoke-exposed, as they are in smokers. The induction of
genes encoding carcinogen metabolizing enzymes simultaneously in an
easily-accessible surrogate tissue as well as the lung suggests the
possibility of expression phenotyping smokers for bioactivating gene
inducibility. If this carcinogen metabolism pathway is indeed relevant to lung
cancer susceptibility, then a high phase I and low phase II enzyme
inducibility phenotype might be hypothesized to confer risk for lung cancer.
The power of studies on carcinogen-metabolizing gene induction in lung cancer
to date have been limited by the number of subjects enrolled, as quality human
lung tissues suitable for expression or activity assays are in short supply.
Additionally, studies of coding sequence polymorphisms in these genes have
presented very mixed results as to conferred risk for lung cancer. This study
proposes to take advantage of newly developed real-time methods for
quantifying gene expression in an appropriate, smoke-exposed epithelium, and
comparing that expression to that in precisely-defined microdissected
smoke-exposed human lung epithelia. Therefore, the specific aims are: 1)
Develop quantitative real-time RT-PCR assays for the evaluation of gene
expression of a panel of carcinogen metabolizing enzymes in buccal mucosa,
including Ahr, ER, CYP1B1, CYP1A1, GSTM1, GSTM3, GSTP1, GSTT1, NQO1. 2) Compare the gene expression in buccal mucosa to simultaneously sampled plasma
assayed for nicotine and cotinine by state-of-the-art LC-MS-MS techniques. 3)
Quantitatively compare the expression of carcinogen metabolizing enzyme genes
from in situ tobacco-exposed human buccal mucosal cells with that from
microdissected human lung bronchial and alveolar epithelial cells also exposed
in situ. 4) Measure the variability of this buccal cell
carcinogen-metabolizing gene expression across individuals, accounting for
expression confounders such as tobacco smoke exposure and dietary
constituents, and thereby identify phase I and phase II high or low
expressors. The long-term goal is to develop a panel of biomarkers in an
easily-accessible, smoke-exposed epithelium that identifies smokers at
high-risk for lung cancer, and thereby allows smoking-cessation,
chemoprevention and early-disease detection strategies to be focussed on those
most at risk.
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