DESCRIPTION (Applicant's Description)
Pancreatic cancer contributes 5 percent of the total cancer death in this
country. It is a deadly disease with little known about the etiology. The
most consistently identified epidemiological risk factor for pancreatic cancer
is cigarette smoking. Dietary and industrial carcinogens have also been
suspected to be involved. Among all human cancers, pancreatic cancer has the
highest frequency (85 percent) of K-ras mutation and this event occurs in the
early stage of tumor development. Half of these mutations are C to A
transition, a point mutation induced by nitrosamines and other alkylating
agents in experimental animals. Nitrosamines are potent inducers of
pancreatic tumors in hamsters but not in rats. Variation in carcinogen
metabolizing enzymes between the two species has been credited for the
difference in their susceptibility to the exposure. Based on this
information, we propose two hypotheses: 1) Exposure to nitrosamines and other
alkylating agents leads to formation of DNA alkylation products which cause K-
ras mutations; 2) individuals with increased susceptibility to such exposure
are at greater risk for pancreatic cancer than are non-susceptible
individuals. To test these hypotheses, we will take a molecular
epidemiological approach with a case-control study. 100 newly diagnosed
pancreatic cancer patients will be matched with 100 non-cancer controls by
age, sex, ethnicity and smoking. We will measure carcinogen exposure by a
detailed questionnaire collecting information on occupation, smoking, alcohol
consumption and dietary history. We will determine genetic polymorphisms of
the carcinogen metabolizing enzymes, cytochrome P450 lAl and 2E1, N-acetyl
transferase 1 and 2, and glutathione S transferase. We will measure DNA
repair capacity by applying two carcinogen-induced DNA damage assays. We will
detect DNA damage derived from exposure to PAH and alkylating agents in the
target tissues of cases. The DNA damage profiles will be analyzed in relation
to K-ras mutation profiles in the tumors. Finally, the epidemiological data
will be analyzed along with the biomarker data to examine the gene and
environmental interactions. The long-term goal of our research is to identify
the genetic and environmental factors that influence the risk of developing
pancreatic cancer, therefore novel strategies can be developed for prevention
and early detection of the disease. This pilot study is intended to set the
stage for a large scale of investigation in the near future.
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