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

Background: 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. Methods: 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. Results: 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 for 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. Conclusions: High marine ω-3 PUFA intake is associated with lower risk for 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.