It is proposed to use the resources of three well-characterized cohort studies with prospectively collected blood specimen banks, the Nurses Health Study, the Health Professionals Follow-up Study, and the Physician's Health Study, to prospectively assess gene-nutrient and other gene-environment interactions in the etiology of colorectal cancer and adenomas. The carcinogen- metabolizing genes the investigators will assay are N-acetyltransferase 2, N-acetyltransferase 1, glutathione S-transferase M1 (GSTM1) and CYP1A1. They hypothesize that """"""""fast acetylator"""""""" NAT2 genotype, a recently described defect in NAT1, homozygous deletions in the GSTM1 gene, and the """"""""extensive metabolizer"""""""" CYP1A1 genotypes are associated with increased risk of colorectal cancer and adenomas. In addition, they will assess interactions of known and suspected colon cancer risk factors with these genotypes, including red meat intake, antioxidant vitamin and carotenoid intake, folate consumption, smoking and alcohol. They expect to identify 604 cases of colorectal cancer and 558 cases of first-adenomatous polyps; each case will be matched by age and race to a control in a nested case-control study. They state they will have greater than 80% power across the three studies to prospectively assess the main effects of these genotypes with colorectal cancer and polyps. They further state that they have substantial power to test for interactions. The investigators state that these studies will be among the first to prospectively test these hypotheses, and provide population-based estimates of attributable risks. They comment that associations with these genotypes would implicate their substrates in cancer etiology, clarifying the specific colon carcinogens in diet. They further comment that identifying gene-diet interactions would suggest dietary interventions that persons with the risk genotypes could make to reduce their risk. They conclude that confirmation of risk genotypes would also be useful in identifying persons at high risk of colon cancer and assist in focusing screening efforts.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070817-04
Application #
2895538
Study Section
Special Emphasis Panel (ZRG4-EDC-1 (01))
Program Officer
Verma, Mukesh
Project Start
1996-08-01
Project End
2001-05-31
Budget Start
1999-06-01
Budget End
2001-05-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Schernhammer, Eva S; Giovannucci, Edward; Kawasaki, Takako et al. (2010) Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer. Gut 59:794-9
Hazra, Aditi; Fuchs, Charles S; Kawasaki, Takako et al. (2010) Germline polymorphisms in the one-carbon metabolism pathway and DNA methylation in colorectal cancer. Cancer Causes Control 21:331-45
Hazra, Aditi; Kraft, Peter; Lazarus, Ross et al. (2009) Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Hum Mol Genet 18:4677-87
Hazra, Aditi; Fuchs, Charles S; Chan, Andrew T et al. (2008) Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk. Cancer Causes Control 19:975-80
Schernhammer, Eva S; Ogino, Shuji; Fuchs, Charles S (2008) Folate and vitamin B6 intake and risk of colon cancer in relation to p53 expression. Gastroenterology 135:770-80
Hazra, Aditi; Chanock, Stephen; Giovannucci, Edward et al. (2008) Large-scale evaluation of genetic variants in candidate genes for colorectal cancer risk in the Nurses'Health Study and the Health Professionals'Follow-up Study. Cancer Epidemiol Biomarkers Prev 17:311-9
Grodstein, Francine; Manson, JoAnn E; Stampfer, Meir J et al. (2008) Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy. Arch Intern Med 168:861-6
Schernhammer, Eva S; Giovannuccci, Edward; Fuchs, Charles S et al. (2008) A prospective study of dietary folate and vitamin B and colon cancer according to microsatellite instability and KRAS mutational status. Cancer Epidemiol Biomarkers Prev 17:2895-8
Hazra, Aditi; Kraft, Peter; Selhub, Jacob et al. (2008) Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet 40:1160-2
Schernhammer, Eva; Wolpin, Brian; Rifai, Nader et al. (2007) Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts. Cancer Res 67:5553-60

Showing the most recent 10 out of 32 publications