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The large variation in cancer rates that exists among ethnic/racial groups in the U.S. constitutes an important public health challenge but also offers unique opportunities for etiologic research. The work of our laboratory is aimed at investigating the genetic and lifestyle factors responsible for some of these risk differences, with the goal of advancing our understanding of the causes, mechanisms and prevention of cancer. This multidisciplinary effort is mainly focusing on lung and colorectal cancers.

Early work showed that migrants to Hawaii experienced a major shift in cancer rates toward the rates of their adoptive country. This observation, reproduced in migrants to other parts of the world, indicated that environment and lifestyle play a predominant role in determining cancer risk. However, environmental exposures are unlikely to explain cancer risk patterns completely. For example, we showed in Hawaii that there remain substantial ethnic differences in the lung cancer risk associated with smoking after adjusting for smoking patterns, dietary habits, occupation and other risk factors (Cancer Epidemiol. Biomarkers Prev. 1992;1:103-7). Since considerable inter-individual variation exists in the activity of enzymes responsible for the activation and detoxification of tobacco carcinogens (e.g., CYP1A1, GSTM1, CYP2E1), we are exploring the associations between lung cancer and common inherited genetic variants (polymorphisms) responsible for a change in the activities of these enzymes. We are also studying the effects of various dietary factors on theses enzymatic pathways in relation to lung cancer risk. A recent analysis showed that a polymorphism in the CYP1A1gene was directly associated with lung squamous cell carcinoma and a polymorphism in the CYP2E1 gene inversely associated with lung adenocarcinoma (Cancer Res. 1998;58:4858-63). Onion intake was also found to be inversely associated with risk of squamous cell carcinoma and to modify the association with CYP1A1, suggesting that the known inhibiting effect of the flavonoid quercetin (present in large quantities in onions) on CYP1A1 may be an important protective mechanism (J. Natl. Cancer Inst. 1999). Studies using various biomarkers of exposure, genetic susceptibility and early biological effects are being initiated to confirm these relationships.

In an attempt to explain the extremely high colorectal cancer risk of Japanese Americans, we explored colorectal cancer associations and dietary habits among Japanese and Caucasians in Hawaii. We observed that red meat and processed meats increased risk for this disease and that Japanese had a significantly greater intake of these foods than Caucasians (Cancer Epidemiol. Biomarkers Prev. 1999;8:45-51; J. Natl. Cancer Inst. Mongr. 1999). This led us to further investigate in a second case-control study the association of colorectal cancer with cooking methods for meat and genetic polymorphisms associated with the metabolic activation of heterocyclic amines, polycyclic aromatic hydrocarbons and nitrosamines, potent mutagens found in well-cooked meat, broiled meat and processed meats, respectively. We found that most of these polymorphisms were two to five times more common in Japanese than in Caucasians. In a preliminary analysis, we also found an association between colorectal cancer and the combined rapid NAT2 and rapid CYP1A2 phenotypes that was limited to individuals consuming their meat well done, suggesting that both exposure and genetic susceptibility may be needed to increase risk. We are attempting to reproduce these associations in a prospective study of about 215,000 Japanese, Caucasian, African-American, Hispanic and Hawaiian residents of Hawaii and Los Angeles who mailed back an epidemiologic questionnaire between 1993 and 1996. Blood samples are being collected from incident colorectal cancer cases and a subset of cancer-free cohort members.

Our findings to date suggest that the interactions of specific genetic and lifestyle factors may play an important role in determining population and individual risks for certain cancers.