Fish Oil Supplementation, Nutrigenomics and Colorectal Cancer Prevention
Condition: Colorectal Adenomatous Polyps
MeSH terms: Adenomatous Polyps
Intervention: Eicosapentanoic acid and docosahexanoic acid; Oleic Acid
Intervention description: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 141.0
Sex: All
Minimum age: 40 Years
Maximum age: 79 Years
Healthy volunteers: No
Keywords: Colorectal Neoplasm

Summary:

      Colorectal cancer is the second leading cause of cancer-related death 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 (COX) pathway to prostaglandin E2 (PGE2), an inflammatory eicosanoid
      overproduced 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 altered through dietary
      changes, genetic factors may also influence this ratio. Recent genetic studies have
      demonstrated that much of the tissue levels of ARA is determined by differences in a gene
      called fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion
      of linoleic acid, the most commonly consumed PUFA in the Western diet, to ARA, and one
      particular genetic variant caller rs174537 is associated with lower fatty acid desaturase
      activity and subsequently lower tissue levels of ARA.

      The study 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 the investigators will recruit 150 participants with
      recently identified adenomatous polyps and conduct a 6-month double blind 3 X 2 factorial
      randomized controlled trial. The first factor will be FADS1 genotype (GG, GT, and TT) and the
      second factor will be fish oil supplementation (fish oil versus placebo). The primary outcome
      will be the change in rectal epithelial cell growth and cell death. Secondary outcomes will
      include rectal epithelial cell expression of genes important in PGE2 production, 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.

      The specific aims include: 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. The investigators 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. The investigators 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
    

Eligibility criteria:

        Inclusion Criteria:

          -  ≥ 40 and < 80 years of age

          -  History of 1 or more adenomatous polyps

          -  Consent to be contacted for future studies

          -  Participants with known genotype for rs174535 in FADS1

          -  Prior participation in the Tennessee Colorectal Polyp Study or the Personalized
             Prevention of Colorectal Cancer Trial

        Exclusion Criteria:

          -  Previously resected colorectal cancer

          -  Coronary artery disease or congestive heart failure

          -  Current metabolic or life-threatening disease

          -  Currently taking fish oil supplements

          -  Inability or unwillingness to stop NSAIDs or ASA during the study

          -  Allergic to fish products

          -  Diagnosis of inflammatory bowel disease

          -  Diagnosis of any cancer (except non-melanoma skin cancer)

          -  Diagnosis of liver or kidney disease

          -  Pregnant or breast feeding