Polyunsaturated fatty acids (PUFAs) have been postulated to impact cancer incidence and survival, but epidemiological evidence remains inconclusive.¹ In a population-based cohort study, extensive data from the United Kingdom (UK) Biobank was used to investigate the association between plasma levels of omega-3 and omega-6 PUFAs with the incidence of overall and 19 site-specific cancers.¹ The findings reveal that both PUFAs are inversely associated with overall cancer risk, with omega-6 linked to 14 site-specific cancers and omega-3 to five, all showing protective effects, except for a positive association between omega-3 and prostate cancer.¹

Multiple animal studies and in vitro studies have suggested that PUFAs may have a protective effect on cancer risk through their regulation of metabolic pathways and inflammatory reactions, altering the membrane composition, and affecting cell growth.^1,2 However, its true association with cancer risk remains controversial, with an umbrella review of 57 meta-analyses reporting only weak evidence to support the inverse associations of omega-3 intake and cancer risks.^1,2 Limitations of current studies include large between-study heterogeneity, insufficient case numbers, short follow-up time, and reliance on self-reported fish oil supplementation or estimated dietary intake, which are prone to recall errors and measurement inaccuracies.¹ This study thus aims to address these limitations by examining objective blood levels of PUFAs in a large prospective cohort with long follow-up time, which may provide a clearer understanding of the roles of omega-3 and omega-6 in cancer risk.¹

The UK Biobank is a large population-based prospective cohort that has followed over 500,000 participants since 2006.¹ A total of 253,138 participants were included in this study, after excluding those with cancer diagnoses at baseline, those who had withdrawn from UK Biobank, and those with missing data on the plasma PUFAs.¹ The participants were followed up for an average period of 12.9 years, during which 29,838 individuals were diagnosed with cancer.¹ The absolute concentrations of plasma PUFAs were assessed using nuclear magnetic resonance (NMR) at the baseline visit and expressed as percentages of total fatty acids (omega-3% and omega-6%).¹

In the main models, both omega-6% and omega-3% were inversely associated with overall cancer incidence, with each standard deviation (SD) increase (3.63% increase) in omega-6% being associated with a 2% reduction in the risk of overall cancer (HR per SD=0.98; 95% CI: 0.96-0.99; p=0.001), while each SD increase (1.55% increase) in omega-3% was associated with a 1% reduction in overall cancer risk (HR per SD=0.99; 95% CI: 0.97-1.00; p=0.03).¹ Similar analyses were performed for 19 site-specific cancers, of which 14 were inversely associated with omega-6% and five with omega-3%, except for prostate cancer which was positively associated with omega-3% (HR per SD=1.03; 95% CI:1.01-1.05; p=0.049).¹

Additional analyses investigating the omega-6/omega-3 ratio found that a higher ratio was associated with an increased risk of overall cancer (p_trend=0.038).¹ The inverse associations of plasma omega-6% were also more pronounced in the younger age group (median age of <58 years) and in women.¹ On the other hand, the inverse associations of plasma omega 3% with overall cancer incidence were stronger in the older age group, in men, and in current smokers.¹

One major strength of this study is the prospective population-based study design in UK Biobank, which provides a large sample size, long follow-up duration, and detailed information on potential confounders.¹ The objective measurements of PUFA in plasma instead of self-reported questionnaires also increase the accuracy of exposure assessment.¹ However, most participants were of European ancestry and White ethnicity, hence caution is needed in generalizing results across other ancestral backgrounds and ethnicities.¹ The number of events for some specific cancer sites was also small which may lead to limited statistical power of the study.¹ As this study only focused on two PUFAs, future studies on other individual PUFAs are also needed.¹

In summary, results from this study indicate inverse associations of plasma omega-3 and omega-6 PUFAs with overall cancer risk.¹ These findings extended to 14 site-specific cancers with omega-6 and five with omega-3 levels which showed protective effects, except for a positive association between prostate cancer and omega-3 levels.¹