Grant Number:	5R01CA072520-02 Interpret this number
Primary Investigator:	Le Marchand, Loic
Organization:	University Of Hawaii At Manoa
Project Title:	Diet, Genetic Susceptibility and Colorectal Adenomas
Fiscal Year:	1998

DESCRIPTION: Consumption of fried meat, particularly red meat, has consistently been associated with colorectal cancer and adenoma in past studies and is common in Hawaiian Japanese. It has recently been proposed that genetic susceptibilities to the heterocyclic aromatic amines (HAAs) and polycyclic aromatic hydrocarbons (PAHs), present in these foods, is determined by several polymorphic genes; thus, these genes may increase the risk of colorectal neoplasms. The susceptible phenotypes for most of these genes are several times more common in Japanese than Caucasians, an observation which could explain the extraordinarily high risk of the Japanese for these tumors. It has also been suggested that heterocyclic amines may activate K-ras, an oncogene that is often found mutated in colorectal neoplasms. The proposed plan is to test these hypotheses in a community-based case-control study of precursor lesions (colorectal adenomata), among largely unselected groups of Japanese and Caucasians, screened by flexible sigmoidoscopy in Hawaii for either the PLCO trial or the Kaiser Permanente HMO. Other hypotheses to be tested include the role of folic acid, methionine, lipids, alpha-tocopherol and other dietary factors in the aetiology of colorectal adenomata. A diet history questionnaire will be administered in person to about 440 almost exclusively incident cases (220 Japanese and 220 Caucasians) with colorectal adenoma and 880 Japanese and Caucasian screened-negative controls, frequency-matched on sex, ethnicity, age, and screening site and date to assess the usual consumption of meat and fish items prepared by high-temperature methods and doneness of meats, in addition to estimating the total intake of energy, nutrients, and other dietary components. 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 (indicative of CYP1A2) and N-acetylation phenotypes. A blood sample will also be collected during the same home visit for genetic analyses. Genotyping for polymorphisms in NAT1, NAT2, CYP1A1, CYP2E1 and GSTM1 will be performed by PCR-based analyses of leukocyte DNA. The genotyping of NAT2 will allow for the characterization of an intermediate risk group, whereas the phenotyping of NAT2 may lead to the identification of a group at particularly high risk. 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 also be stored for future examination of other germline and somatic mutations.