Project Number: 1950-51520-008-06
Project Type: Grant

Start Date: Oct 01, 2006
End Date: Sep 30, 2009

Objective:
To measure Vitamins B-6, B-12, and Homocysteine in the Prostate, Lung, Ovarian, and Colorectal Cancer Screening trial to determine if they modify the relationship between benzene exposure and hematoxicity and chromosomal damage and to evaluate the relationship between polymorphisms in genes involved in one-carbon metabolism, folate and homocysteine levels. To determine methylmalonic acid (MMA) in plasma from the Prostate, Lung, Ovarian, and Colorectal Cancer Screening Trial(PLCO) participants for defining association between vitamin B12 status and colorectal cancer (CRC) risk.

Approach:
A. The Prostate, Lung, Ovarian, and Colorectal Cancer Screening Trial) cohort (PLCO) includes 160,000 men and women randomized either to a series of cancer screening procedures or regular medical surveillance. Subjects assigned to the screening arm of PLCO who have any abnormality at the baseline sigmoidoscopy are referred for a complete colonoscopy. Currently available for analysis are 3500 men and women with a confirmed, first-time adenoma in the descending colon or rectum, including 1350 with an aggressive adenoma, based on size and pathology. These cases will be compared with the 35,000 men and women with no colorectal abnormalities at or prior to the initial screening. Usual diet, vitamin supplement use, alcohol use, and colorectal cancer risk factors were all assessed at baseline. We propose to examine the relationship of circulating levels of folate, B-6, and B-12 to risk of aggressive adenoma, using both the prevalent and incident series. Circulating homocysteine will be used as a biomarker of folate deficiency and inefficient one-carbon metabolism. In addition, a number of common polymorphisms, and possibly haplotypes, for one-carbon metabolism genes will be measured in the NCI Core Genotyping Facility. We will thus be able to explore, in the controls, the interrelationships of homocysteine, folate, B-6, and B-12 with various genetic patterns. B. In 2000, about 90 workers, including those exposed to benzene and unexposed controls, were studied in Tianjin, China. Air monitoring for benzene was carried out over several months, urine was collected to evaluate benzene metabolite levels to enhance overall exposure assessment, and blood samples were collected. In addition, a questionnaire requesting information on lifestyle and other potentially relevant risk factors and a food frequency questionnaire were administered. Plasma was separated, stored at -70 C and shipped on dry ice to the National Cancer Institute. In 2001, about 345 subjects were studied using the same approach, with the exception that blood samples were stabilized with ascorbic acid for folate analysis. About 28 subjects were studied twice, once in 2000 and again about one year later in 2001. The blood samples have been or are in the process of being analyzed for peripheral blood counts, lymphocyte subsets and unbanded chromosomal aberrations in peripheral lymphocytes. Further, in a subgroup selected to represent highly exposed workers and controls, chromosomal aberrations are being analyzed in cultured lymphocytes and in granulocyte precursor cells cultured from peripheral blood. In addition, a wide range of polymorphisms in genes relevant for one-carbon metabolism are being analyzed in DNA from all subjects.