DESCRIPTION (provided by applicant): Colon cancer is the second leading cause
of cancer deaths in the U.S. Despite rapid advances in human genetics, critical
questions about genetic susceptibility to, and prevention of, colon cancer
remain unanswered, particularly for African-Americans, who have a higher
incidence and mortality rate. Our primary objective is to evaluate genetic
susceptibility and environmental factors that might explain the diverging
incidence and mortality trends in blacks and whites. Our secondary objective is
to assess the mechanisms involved in gene-gene and gene-environment
interactions and to identify high-risk (sub)populations and modifiable risk
factors for colon cancer. Then it may be possible to closely tailor
etiology-driven preventive strategies to the specific genetic defects
conferring individual risk. We will evaluate the association between colon
cancer risk and two phase II metabolic detoxification genes (GSTM]/T1), two
base excision repair genes (XRCC1 and APE), a gene in double-strand
break/recombination repair (XRCC3), and a nucleotide excision repair gene
(XPD). The proposed study will use the existing genomic DNA samples and
exposure data collected in the NCI-funded North Carolina Colon Cancer Study
(NCCCS) (CA 66635). The NCCCS is a well-designed, large population-based,
case-control study in a 33-county area of North Carolina with 800 newly
diagnosed colon cancer cases and 800 age- and race-matched controls (50 percent
blacks and 50 percent whites). The parent study is on target to complete sample
and data collection by our proposed start date of January 1, 2002. The high
percentage of black participants (50 percent) provides the unique opportunity
to study specific risk factors in African-Americans, an understudied population
at increased risk of fatal colon cancer. The large sample size provides
substantial statistical power for the assessment of gene-gene and gene-exposure
interactions in colon cancer risk. Our preliminary pilot data demonstrated
black-white differences in genotype distributions and environmental exposures.
We also observed gene-gene and gene-environment interactions in colon cancer
risk. This proposed research will fill the gap between colon cancer risk
assessment and prevention. Confirmation of risk profile(s) will be useful in
identifying persons at high risk of colon cancer for screening and
intervention. Characterization of gene-environment interactions will
provideeffective strategies for dietary and lifestyle interventions,
particularly in genetically susceptible (sub)populations.
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