Colorectal cancer is the second leading cause of cancer-related mortality within the United States. Animal models and observational studies have suggested that marine-derived n-3 polyunsaturated fatty acids [PUFA] such as eicosapentanoic acid [EPA] and docosahexanoic acid [DHA] may reduce the risk of colorectal cancer. In addition, it may be the relative proportion of n-3 to n-6 PUFAs that best determines the chemopreventive effects of fish oils. This ratio is important because the n-6 PUFA, arachidonic acid (ARA), is converted via the cyclo-oxygenase pathway to prostaglandin E2 (PGE2), an inflammatory eicosanoid aberrantly produced in colorectal neoplasms while EPA is converted to the anti-inflammatory prostaglandin E3 (PGE3). While the ratio of n-6 to n-3 PUFAs can be manipulated through dietary measures, genetic factors may also influence this ratio. Recent genome-wide association and haplotype studies have demonstrated that up to 28% of the additive variance in tissue levels of ARA is explained by variants in a single gene, fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion of linoleic acid, the most commonly consumed PUFA, to ARA, and homozygotes for the T allele (population frequency of 13%, HapMap -CEU) in rs174537 have lower fatty acid desaturase activity and subsequently lower tissue levels of ARA. Our hypothesis is that individuals with genetically determined lower activity of FADS1 will derive greater benefit from fish oil supplementation than individuals with higher FADS1 activity because of lower tissue levels of ARA and subsequently a more favorable n-6 to n-3 PUFA ratio. To test this hypothesis we will recruit 150 participants with recently identified adenomatous polyps and conduct a 6-month double blind 3 X 2 factorial randomized controlled trial. Our first factor will be FADS1 genotype (GG, GT, and TT) and our second factor will be fish oil supplementation (fish oil versus placebo). Our primary outcome will be the change in rectal epithelial cell proliferation as measured by Ki-67 labeling and rectal crypt apoptosis as measured by TUNEL. Secondary endpoints will include rectal epithelial cell expression of COX-2 and 15-PGDH, rectal cell production of PGE2 and PGE3, rectal mucosal tissue levels of fatty acids, and changes in biomarkers of inflammation (C-reactive protein), adipokines (leptin, adiponectin), and markers of insulin sensitivity.
Our specific aims i nclude: 1) to determine the efficacy of fish oil supplements on rectal epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil supplementation for colorectal cancer chemoprevention. Our long-term objectives are to determine genetic factors that might influence the efficacy of fish oil supplementation in order to conduct a more definitive adenoma recurrence trial using marine-derived n-3 PUFAs. We anticipate that fish oil will have anti-neoplastic effect and individuals with low FADS1 activity will have a greater response compared to individuals with high FADS1 activity.

Public Health Relevance

Colorectal cancer is the second leading cause of cancer-related mortality within the United States. Fish oils may be beneficial for cancer chemoprevention through their anti-inflammatory properties, however;variations in genes related to polyunsaturated fatty acid biosynthesis may attenuate these effects. This study will investigate the nutrigenomics of fish oil supplementation in colorectal cancer chemoprevention and may have implications beyond cancer prevention as fish oil is being actively investigated for cardiovascular, psychiatric and metabolic diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Seifried, Harold E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Murff, Harvey J; Roumie, Christianne L; Greevy, Robert A et al. (2018) Metformin use and incidence cancer risk: evidence for a selective protective effect against liver cancer. Cancer Causes Control 29:823-832
Rifkin, Samara B; Shrubsole, Martha J; Cai, Qiuyin et al. (2017) PUFA levels in erythrocyte membrane phospholipids are differentially associated with colorectal adenoma risk. Br J Nutr 117:1615-1622
Coppola, John-Anthony; Shrubsole, Martha J; Cai, Qiuyin et al. (2015) Plasma lipid levels and colorectal adenoma risk. Cancer Causes Control 26:635-43
Murff, Harvey J; Edwards, Todd L (2014) Endogenous Production of Long-Chain Polyunsaturated Fatty Acids and Metabolic Disease Risk. Curr Cardiovasc Risk Rep 8:
Murff, Harvey J; Shrubsole, Martha J; Cai, Qiuyin et al. (2012) Dietary intake of PUFAs and colorectal polyp risk. Am J Clin Nutr 95:703-12