This is a revised renewal application for our ongoing case-control study
of nutritional and other risk factors for adenomatous polyps of the large
bowel. Subjects are asymptomatic persons who attended a sigmoidoscopy
screening clinic at one of two Kaiser Permanente-Southern California
clinical centers. Cases (n=530) are persons with a first-time diagnosis of
at least one adenomatous polyp confirmed by biopsy. Controls (n=530) are
subjects found to have no adenomatous polyp at sigmoidoscopy and with no
history of large bowel neoplasia. Data are obtained from a food frequency
questionnaire, in-person interview, fasting blood sample, and pathology
material (including the recent addition of tumor blocks). In the current
study, we have exceeded the sample size goal and achieved very high
response rates (84% for cases, 82% for controls) for a study of this
Our objective for this renewal is to investigate gene-environment
interactions, including both "inherited susceptibility genes" and
"metabolic genes". During the next grant period, we plan to focus on a set
of mutator genes (hMSH2, hMLH1, PMS1, PMS2), NAT1, NAT2, and GST. hMSH2 is
a relatively common gene believed to be a major cause of HNPCC and other
forms of colon cancer/polyps. Molecular analyses of these genes
(principally looking for microsatellite instability and sequencing) are
planned that would enable us to a) estimate the prevalence of
microsatellite instability in polyps b) the number and type of mutations
in hMSH2, hMLH1, and PMS, c) the prevalence of these mutations. d) the
penetrance/risk associated with mutations, and e) identify factors that
may affect penetrance of these genes (including other genes, such as k-
ras, and environmental exposures). NAT helps determine acetylator status.
We propose to determine genotypes of NAT1 and NAT2. We will also genotype
GST1. This will enable us to estimate main effects for NAT and GST, and
interactions with protein intake in general, red meat, and tobacco smoke.
In order to achieve adequate statistical power to detect interactions. we
propose to double our sample size to 1200 cases and 1200 controls, using
essentially the same staff and protocol as our ongoing study. Achieving
this sample size would also enable us to begin more informative
explorations of nutrient-nutrient and physical activity-nutrient
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