Dietary Long-Chain Omega-3s Linked to Lower Risk of Colorectal Polyps in Women

[frame src="/wp-content/uploads/images/PUFA4.12_Photo12.1.png" alt="" width="216" height="262" align="right"]The most effective preventive strategy for colorectal cancer, which is the third most common cancer in the U.S., is the detection of its earliest abnormalities, polyps in the colon or rectum. These precancerous lesions are detected by colonoscopy, a visual inspection of the colon. The doctor will remove any abnormal polyps during the procedure. Because colorectal cancer usually does not reveal itself until the condition is advanced, looking for its earliest warning signs offers the greatest protection. A recent study reported a 77% lower risk of the disease in adults 50 years of age and older who had had a colonoscopy in the preceding 10 years. Diet has been implicated in the risk of colorectal cancer for decades, but research continues to be inconclusive. The strongest evidence of a link between diet and reduced risk of colorectal cancer has been with omega-3 (n-3) PUFAs, especially with the long-chain (LC) n-3 PUFAs found predominantly in fish and shellfish. These fatty acids have been associated with improved efficacy or tolerance of cancer chemotherapy and radiation treatment. They also have beneficial associations with reduced inflammation, less oxidative stress, restrained eicosanoid metabolism, [frame src="/wp-content/uploads/images/PUFA4.12_Callout29.png" alt="" width="191" height="177" align="left"]increased cancer cell apoptosis in vitro, and more favorable gene expression. Much research with n-3 LC-PUFAs has been conducted in cultured cells and animal models, with findings in humans varying considerably from those observed in cells or animals. Studies in human populations with high consumption of fish have reported a significantly lower risk of colon cancer among Japanese adults with the highest n-3 LC-PUFA intakes, but higher risk of colorectal cancer in a cohort of Singapore Chinese men and women with high intakes of n-3 LC-PUFAs. Intakes of total or individual n-6 and n-3 PUFAs were not associated with colorectal cancer risk in the Shanghai Women’s Health Study. A different study from Japan reported no association between fish consumption and the risk of colorectal cancer. A meta-analysis of fish and n-3 PUFA intakes and colon cancer risk reported a small reduction in risk that was more pronounced in women than men. EPA supplementation (2 g/day) in patients with familial adenomatous polyposis, an inherited cancer of the large colon and rectum, who had had a colectomy was associated with a 22% reduction the number of rectal polyps observed in rectal tissue over 6 months compared with placebo controls whose condition worsened. The promising and more consistent results from cell and animal studies continue to drive the quest for interventions that might reduce the risk of colorectal cancer before it becomes established. For this, n-3 LC-PUFAs remain the leading candidate. [frame src="/wp-content/uploads/images/FOL4.12_Callout30.png" alt="" width="190" height="175" align="right"]One explanation why n-3 LC-PUFAs might reduce the risk of colorectal cancer is their effect in counteracting the inflammatory pathways promoted by the metabolism of arachidonic acid, which is converted to prostaglandin E₂ (PGE₂) by the action of cyclooxygenase. In most colorectal cancers the expression of this enzyme is elevated. As a result, there is an overproduction of PGE₂, which can be assessed by measuring the urinary excretion of its metabolite, prostaglandin-M. In the Shanghai Women’s Health Study, urinary prostaglandin-M excretion was more than 50% higher in cases of colorectal cancer compared with controls. A recent report found a 2.5-fold higher risk of advanced or multiple small tubular adenomas in patients with high levels of prostaglandin-M excretion compared with patients having low urinary levels. The association was strongest in women. In the present article, Harvey Murff and colleagues at Vanderbilt University School of Medicine, U.S. examined the association between the consumption of n-6 and n-3 PUFAs, the excretion of prostaglandin-M and the risk of having adenomatous polyps as determined by colonoscopy. Participants in the study were selected from those enrolled in the Tennessee Colorectal Polyp Study, a colonoscopy-based case-control study of 40- to 75-year-old adults scheduled for a colonoscopy. Participants with genetic colorectal cancer or familial adenomatous polyposis or a history of inflammatory bowel disease or any cancer other than nonmelanoma skin cancer were excluded. Of the 12,585 eligible participants, 7,621 agreed to participate. The average age of participants was 58 years. Polyps were classified as adenomatous (benign), hyperplastic, mixed or other. The investigators obtained demographic and medical history information by telephone interview and dietary intakes from a participant-administered food frequency questionnaire. Complete medical history and dietary intake data were available for 5,307 participants. Of these, 3,166 were polyp-free controls and 2,141 had polyps, including 1,597 with adenomatous and 544 with hyperplastic polyps. Urinary prostaglandin-M was measured using liquid chromatography and tandem mass spectrometry. Risk of developing polyps was determined from unconditional logistic regression models using data for PUFA consumption. All statistical models were adjusted for age, race, body mass index, total energy intake, cigarette and alcohol use, educational attainment and 8 other variables. Data for each sex were analyzed separately. In both sexes, participants with polyps were more likely than controls to be current smokers, consume less calcium and have significantly lower intakes of n-3 LC-PUFAs. The highest average daily n-3 LC-PUFA intake for men was 170 mg/day (controls) and for women, only 100 mg/day. Other variables, such as educational attainment, body mass index and total energy intake differed significantly between cases and controls, and between sexes. [frame src="/wp-content/uploads/images/PUFA4.12_Callout31.png" alt="" width="203" height="206" align="left"]There were no significant associations between the intakes of linoleic or arachidonic acid and the risk of developing any type of polyp in men or women. Among women, those with the highest intake of n-3 LC-PUFAs had a 33% lower risk of adenomatous polyps, both advanced and nonadvanced types, compared with women in the lowest consumption category (P = 0.01). In men, but not in women, there was a significantly greater risk (50%) of developing hyperplastic polyps among those in the highest compared with the lowest quintile of alpha-linolenic acid intake (P = 0.03). In men, the consumption of n-3 LC-PUFAs was not significantly associated with the risk of developing either type of polyp. The investigators confirmed that higher intakes of n-3 LC-PUFAs were significantly associated with lower concentrations of urinary prostaglandin-M, the metabolite of PGE₂, in women, but not in men. No other dietary fatty acids were associated with urinary prostaglandin-M concentrations in men or women. Some evidence suggests that the consumption of fish oil is associated with reduced production of PGE₂ in rectal cells of healthy adults. This case-control study demonstrated a significant inverse association between higher consumption of n-3 LC-PUFAs and a lower risk of adenomatous polyps in women, but not men. The association is striking because fish and n-3 LC-PUFA intakes were relatively low in this population sample. However, the authors reported that women in the highest quintile of n-3 LC-PUFA consumption had a median intake of 232 mg/day and ate 3 servings of fish per week, on average. This n-3 LC-PUFA intake is approximately the amount recommended for the protection of cardiovascular health in healthy adults. Caution about quantitative estimates of n-3 LC-PUFA consumption from food frequency questionnaires is warranted. There is some suggestion from the literature that higher serum DHA concentrations in Japanese adults may be associated with fewer colorectal adenomas in men and women, but a prospective study reported an inverse association between n-3 LC-PUFA consumption and risk of distal colorectal adenoma in women, which did not reach statistical significance. Overall, data on this topic in humans are scarce. The investigators also observed the lowest urinary concentrations of prostaglandin-M in women with the highest intakes of n-3 LC-PUFAs. This relationship was not observed in men, but the reason for this sex difference is unclear. Finally, an intriguing observation in this study was the positive association in men between higher intakes of alpha-linolenic acid and a 50% greater risk of hyperplastic polyps. Alpha-linolenic acid has a checkered past for its associations with various cancers. In some studies, particularly of prostate cancer, higher consumption has been linked to higher risk, but in others high intakes were associated with a lower risk or were not associated with risk. A recent report from a nested case-control study on gastric cancer in the European Prospective Investigation into Cancer, observed a 3-fold greater risk for this cancer among participants in the highest quartile of alpha-linolenic acid consumption. Others reported an inverse association between the risk of bladder cancer and consumption of alpha-linolenic acid. Total and individual n-3 PUFAs, including alpha-linolenic acid, were inversely associated with colorectal cancer risk in a case-control study in Japan. Therefore, the inconsistent observations relating alpha-linolenic acid intakes to cancer risks continue. Until we have a clearer understanding of the mechanisms of action in the development of these cancers, additional observations linking alpha-linolenic acid to risks of cancer or pre-cancerous lesions are unlikely to resolve the discrepant data. The Murff study contributes important data with beneficial implications for the prevention of colorectal adenomas in women. These findings need confirmation by other research groups, long-term intervention studies to determine whether n-3 LC-PUFAs might reduce the risk of colorectal cancer in women and additional work to explain why men and women respond differently. Murff HJ, Shrubsole MJ, Cai Q, Smalley WE, Dai Q, Milne GL, Ness RM, Zheng W. Dietary intake of PUFAs and colorectal polyp risk. Am J Clin Nutr 2012;95:703-712. PubMed WORTH NOTING Trikalinos TA, Lee J, Moorthy D, Yu WW, Lichetenstein AH, Chung M. Agency for Healthcare Research and Quality. 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