Dataset Information

Marine ω-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability.

ABSTRACT: Chronic inflammation is involved in the development of colorectal cancer (CRC) and microsatellite instability (MSI), a distinct phenotype of CRC. Experimental evidence indicates an anti-inflammatory and antineoplastic effect of marine ω-3 polyunsaturated fatty acids (PUFAs). However, epidemiologic data remain inconclusive. We investigated whether the association between marine ω-3 PUFAs and CRC varies by MSI-defined subtypes of tumors in the Nurses' Health Study and Health Professionals Follow-up Study. We documented and classified 1125 CRC cases into either MSI-high tumors, in which 30% or more of the 10 microsatellite markers demonstrated instability, or microsatellite-stable (MSS) tumors. Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of MSS tumors and MSI-high tumors in relation to marine ω-3 PUFA intake. All statistical tests were two-sided. Marine ω-3 PUFA intake was not associated with overall incidence of CRC. However, a statistically significant difference was detected by MSI status (P heterogeneity = .02): High marine ω-3 PUFA intake was associated with a lower risk of MSI-high tumors (comparing ≥0.30g/d with <0.10g/d: multivariable HR = 0.54, 95% CI = 0.35 to 0.83, P linearity = .03) but not MSS tumors (HR = 0.97, 95% CI = 0.78 to 1.20, P linearity = .28). This differential association appeared to be independent of CpG island methylator phenotype and BRAF mutation status. High marine ω-3 PUFA intake is associated with lower risk of MSI-high CRC but not MSS tumors, suggesting a potential role of ω-3 PUFAs in protection against CRC through DNA mismatch repair. Further research is needed to confirm our findings and elucidate potential underlying mechanisms.

SUBMITTER: Song M

PROVIDER: S-EPMC4402363 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ImportanceMarine ω-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid, possess potent immunomodulatory activity and may protect against cancer development. However, evidence relating marine ω-3 PUFAs to colorectal cancer (CRC) risk remains inconclusive.ObjectiveTo test the hypothesis that marine ω-3 PUFA intake may be associated with lower risk of CRC subsets characterized by immune infiltrate.Design, setting, and participantsThis prospective cohort study was conducted among participants in the Nurses' Health Study (1984-2010) and Health Professionals Follow-up Study (1986-2010).ExposuresIntake of marine ω-3 PUFAs.Main outcomes and measuresIncidence of CRC characterized by CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ T-cell densities in tumor tissue, measured by immunohistochemical and computer-assisted image analysis.ResultsAmong 173 229 predominantly white participants, 125 172 with 2 895 704 person-years of follow-up provided data about marine ω-3 PUFA intake every 4 years through a validated food frequency questionnaire and followed up for incident CRC evaluation. Of 2504 CRC cases, we documented 614 (252 men, 362 women) from which we could assess T-cell infiltration in the tumor microenvironment. The inverse association of marine ω-3 PUFAs intake with CRC risk differed according to FOXP3+ T-cell infiltration: compared with intake of less than 0.15 g/d of marine ω-3 PUFAs, intake of at least 0.35 g/d was associated with a multivariable hazard ratio (HR) of 0.57 (95% CI, 0.40-0.81; P < .001 for trend) for FOXP3+ T-cell-high tumors. In contrast, the HR for FOXP3+ T-cell-low tumors was 1.14 (95% CI, 0.8-1.60) (P = .77 for trend; P = .01 for heterogeneity). No statistically significant differential association was found for high-density tumors (compared with low-density tumors) according to CD3+, CD8+, or CD45RO+ cell density (P ≥ .34 for heterogeneity for all comparisons). In functional assays, the suppressive activity of regulatory T cells was approximately 2-fold lower (T-effector-cell proliferation, ≥64% vs 38%) when preincubated with docosahexaenoic acid at 50μM, 100μM, and 200μM concentrations than without docosahexaenoic acid (P < .001 for all comparisons).Conclusions and relevanceHigh marine ω-3 PUFA intake was associated with lower risk of CRC with high-level, but not low-level, FOXP3+ T-cell density, suggesting a potential role of ω-3 PUFAs in cancer immunoprevention through modulation of regulatory T cells.

Project description:Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10-4] and ?-linolenic acid (ORALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10-5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10-3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10-2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

Dataset Information

Marine ω-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets