AROMATIC AMINES AND COLON CANCER RISK--GENETICS

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Consumption of fried meat, particularly red meat, has consistently been associated with colorectal cancer in past studies and are frequently consumed by Hawaii Japanese. It has recently been proposed that genetic susceptibilities to heterocyclic aromatic amines (present in these foods), determined by the N-acetyltransferase (NAT) and, possibly, N-oxidation (P4501A2) polymorphisms, may increase the risk of colorectal cancer. Since the susceptible NAT phenotype is twice as common in Japanese as in Caucasians, this could explain the unexpectedly high risk of the Japanese for this disease. It has also been suggested that aromatic amines may activate ras oncogenes, genes that are often found mutated in colorectal tumors. We propose to test these hypotheses in a large population-based case-control study of colorectal cancer among Japanese and Caucasians in Hawaii. A diet history questionnaire will be administered to about 967 cases (574 Japanese and 393 Caucasians) with adenocarcinoma of the large bowel and 967 Japanese and Caucasian population controls, frequency-matched on sex and age, to collect the usual consumption of meat and fish items prepared by high-temperature methods and information on doneness of meats, in addition to estimating the total intake of energy, nutrients, and other dietary components. This study design will provide adequate power to test the associations of various heterocyclic amine-containing foods, fast N- acetylation phenotype/genotype and fast N-oxidation phenotype with cancer at various sites in the large bowel and with specific somatic K-ras mutations. Interactions with race and age will also be tested. Finally, because of its unmatched design, this study will be able to assess the fraction of interethnic risk difference attributable to these dietary and genetic factors. Phenotyping of the subjects will involve the consumption of two cups of coffee and collection of a single urine sample five hours later. These samples will be assayed by HPLC to determine the N-oxidation and N- acetylation phenotypes. A blood sample will also be collected during the same home visit for genetic analyses. The NAT2 genotyping will be performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism analyses of leucocyte DNA. Allele-specific PCR amplification will also be used to identify mutations at codons 12 and 13 of the K-ras gene in tumor tissue from the cases. DNA will be stored for future examination of other germline and somatic mutations.