Plasma fatty acid associated with risk of gastrointestinal cancer: a prospective cohort study from UK Biobank

Introduction

Gastrointestinal (GI) cancer is currently one of the main causes of cancer death, with a large number of cases and a wide range of anatomical sites. According to the Global Cancer Observatory (GLOBOCAN) statistics, about 5 million new GI cancer cases and 3.5 million deaths were recorded in 2020 (1). Although significant advances have been made in diagnosis and treatment, prognosis remains poor with the vast majority of patients diagnosed in advanced disease stages.

In response to this substantial global burden, authoritative international organizations have developed evidencebased guidelines for cancer prevention. In 2018, the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) jointly released their third expert report, which synthesized data from 51 million individuals and 3.5 million cancer cases (2,3). This comprehensive analysis provided convincing evidence for several modifiable risk factors associated with GI carcinogenesis, including adiposity, alcohol consumption, intake of red and processed meat, and insufficient dietary fiber. Notably, the WCRF/AICR report estimated that approximately 40% of all cancer cases could be prevented by following these evidence‑based recommendations. Nevertheless, despite extensive research on dietary patterns, the specific roles of distinct fatty acid (FA) classes—particularly polyunsaturated fatty acids (PUFAs)—in the prevention of GI cancers remain controversial and have not been fully addressed in current clinical and public health guidelines.

FAs play an essential role in health. They include saturated fatty acids (SFAs), monounsaturated fatty acids (MFAs), and PUFAs, comprising hydrocarbon chains terminating with carboxyl groups (4). FAs play pivotal roles in various metabolic pathways, including energy storage, membrane biosynthesis, gene regulation, and the formation of signaling molecules (5). FA metabolic reprogramming is a hallmark of GI cancers. SFAs promote tumor proliferation by upregulating de novo lipogenesis enzymes, yet their excess intake may induce chemoresistance by altering membrane fluidity and accumulating triglycerides/cholesterol esters in resistant cells (6,7). MFAs are enriched in therapy-resistant tumors. Their oxidation generates volatile organic compounds that serve as non-invasive biomarkers for mammalian target of rapamycin (mTOR) inhibitor response. Moreover, MFAs increase membrane unsaturation, shielding cancer cells from ferroptosis—an iron-dependent cell death process (8,9). PUFAs are substantial components of the diet, contributing to about 4–11% of total energy intake in Europe (10).

PUFAs are important precursors for eicosanoid hormones and regulate several processes implicated with cancer and other diseases, including inflammation, thrombosis and insulin resistance (11,12). However, the biological effects of different PUFA classes are complex and sometimes contradictory. Omega-6 PUFAs, particularly linoleic acid, serve as precursors for pro-inflammatory eicosanoids and have been hypothesized to promote inflammation-associated carcinogenesis (13). Conversely, omega-3 PUFAs exhibit anti-inflammatory properties and have demonstrated tumor-suppressive effects in preclinical models (14). Recent evidence suggests that this dichotomy may be oversimplified, as the net biological effect depends on host factors such as 15-lipoxygenase-1 (ALOX15) expression, which modulates the conversion of PUFAs to resolvins and other specialized pro-resolving mediators (15). This host-factor dependency may explain the conflicting results from epidemiologic studies investigating PUFA-cancer associations.

Emerging evidence suggests that subclinical tumors can induce systemic metabolic reprogramming years prior to clinical diagnosis. For instance, tumor-derived extracellular vesicles and particles have been demonstrated to dysregulate hepatic FA metabolism, thereby promoting inflammation and fatty liver formation through palmitic acid-mediated tumor necrosis factor (TNF) secretion by Kupffer cells (16). Such preclinical observations raise the critical possibility that alterations in circulating FA profiles may reflect the early metabolic sequelae of occult malignancies, rather than serving as causal risk factors for cancer development. The prospective design of the UK Biobank—characterized by baseline blood collection between 2006 and 2010, coupled with long-term follow-up via national cancer registries—affords a unique opportunity to address this concern through sensitivity analyses that exclude events occurring during the early follow-up period (17).

To date, epidemiologic data regarding the association between plasma FAs and GI cancer risk remain limited, and focused primarily on colorectal cancer (CRC). The role of specific PUFA subclasses in gastric, esophageal, and liver cancers remains particularly understudied. To address these knowledge gaps, we assessed the association between plasma FAs and GI cancer risk in the UK Biobank, involving 91,239 adults. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2763/rc).

Methods

Study setting and participants

The UK Biobank is a population-based cohort study that aims to improve the prevention, diagnosis and treatment of a wide range of diseases. The study has collected extensive genetic and clinical data from around 500,000 participants across the UK who were aged between 40 and 69 years at the time of recruitment in 2006–2010. Details of the study design, data collection and processing are described elsewhere (18,19). Access to the data was granted by UK Biobank application number 91734. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Plasma FAs exposure and other covariates

At baseline, approximately 120,000 Ethylene diamine tetraacetic acid (EDTA) plasma samples were randomly selected and stored at −80 ℃. Plasma FA concentrations were measured by a high-throughput nuclear magnetic resonance (NMR)-based metabolic biomarker profiling platform provided by Nightingale Health Ltd. we utilized FA measurements expressed as molar percentages of total FAs. Detailed information regarding biomarker measurements and quality control can be viewed at https://biobank.ctsu.ox.ac.uk/crystal/label.cgi?id=220.

Covariates, including age, sex, body mass index (BMI), Townsend deprivation index (TDI), smoking status, alcohol consumption, family history of cancer, educational level, history of type 2 diabetes, lifestyle scores (Table S1) (20), and relevant remaining plasma FAs, were assessed through the touchscreen questionnaire and physical measurements.

GI cancer ascertainment

Incident GI cancer cases in the UK Biobank were identified through the national cancer registries, utilizing the International Classification of Diseases 10 (ICD-10). The ICD-10 codes for each cancer are detailed in Table S2.

Statistical analysis

The duration of follow-up was calculated from the enrollment date until either censoring or the first cancer diagnosis. Censoring events included death, withdrawal from the study, loss to follow-up, or the end of follow-up period (December 31, 2020, for England, and November 30, 2021, for Scotland), whichever came first. Exclusion of residual cancers from individual cancer analyses.

There were 502,368 UK Biobank participants before the exclusion of any patients. Exclusion criteria: (I) diagnosed with GI or other cancers before enrolment in the cohort; (II) missing clinical and FA information; (III) suffering from other types of cancer. The screening process and results are shown in Figure 1.

Figure 1 Screening process and results of research objects.

We conducted multivariable Cox regression analyses to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for GI cancer risk according to quartiles or per 1 standard deviation (1− SD) increment of plasma FAs. The proportional hazard assumption was evaluated using Schoenfeld residuals (21).

Subgroup analyses were performed to explore the potential modifying effects of covariates on associations between plasma PUFAs and GI cancer. Specifically, the primary analysis was extended to consider subgroups based on sex, age, and BMI.

We conducted sensitivity analyses as following: adjusted for chronic infection status; excluding participants who developed incident GI cancer within the first 2 years to minimize the potential influence of reverse causation; using multiple imputation method in the full model to eliminate selection bias.

We conducted subtype-specific analyses in colon cancer and rectal cancer according to anatomical site.

Analyses were performed using R software (version 4.3.1), with statistical significance set at the 2-sided 0.05 level.

Results

Characteristics of the study population

Baseline characteristics of 1,519 cases and 89,720 controls in the UK Biobank cohort were shown in Table 1. The total follow-up was 14.3 years, with a median follow-up of 11.8 years. Cases were significantly older (60.8 vs. 55.5 years), more likely male (58.2% vs. 45.8%), and had higher BMI (28.3 vs. 27.4 kg/m²; all P<0.001). Cases showed higher family history of GI (13.6% vs. 10.6%) or other cancers (26.5% vs. 23.6%; P<0.001), lower college attainment (31.1% vs. 34.3%; P=0.008), and higher smoking prevalence (56.8% vs. 43.6% ever-smokers; P<0.001). Diabetes was more frequent in cases (20.0% vs. 8.3%; P<0.001), and lifestyle scores differed significantly (P<0.001) with fewer cases having the healthiest score (32.3% vs. 36.4% for score 5). TDI showed no significant difference (P=0.20).

The baseline demographic and lifestyle characteristics of the UK Biobank participants, stratified by plasma PUFA quartiles, are presented in Table 2. Significant positive trends were observed across increasing PUFA quartiles for age and the proportion of female participants (P<0.001 for both). Furthermore, higher PUFA levels were associated with a higher socioeconomic status, improved lifestyle score, and a lower prevalence of diabetes (P<0.001 for all). Trends towards lower rates of current smoking and alcohol abstinence were also significant (P<0.001). While a small but significant difference in BMI was detected (P<0.001), no significant trend was observed for educational attainment (P>0.05).

Higher quartiles of SFA and MFA were associated with adverse cardiometabolic and lifestyle profiles, including elevated BMI, higher rates of current smoking, a U-shaped prevalence of diabetes, poorer lifestyle scores, and lower educational attainment (Tables S3,S4). In contrast, higher quartiles of PUFA—especially OMEGA3—were correlated with favorable trends, such as a lower prevalence of diabetes, reduced smoking, improved lifestyle scores, and higher socioeconomic status (Table S5,S6). Across all FA types, higher quartiles were significantly associated with increased age and lower socioeconomic status (all P<0.001 for trend). A pronounced shift toward a higher proportion of females was observed in ascending PUFA quartiles. Overall, significant dose-response relationships were evident for cardiometabolic and lifestyle factors across all FA classes.

Association between different plasma FAs and incident GI cancer

During the follow-up, 1,519 participants were newly diagnosed with GI cancer. The results showed that plasma PUFAs were associated with a lower risk of overall GI cancer (fully adjusted HR =0.79; 95% CI: 0.71–0.87), esophageal cancer (fully adjusted HR =0.68; 95% CI: 0.53–0.88), CRC (fully adjusted HR =0.82; 95% CI: 0.70–0.95) and liver cancer (fully adjusted HR =0.66; 95% CI: 0.46–0.93) (Table 3). Furthermore, plasma SFAs exhibited a positive association with overall GI cancer risk, as well as esophageal cancer (Table S7). However, plasma MFAs, OMGEA3 PUFAs and OMGEA6 PUFAs were not statistically associated with GI risk (Tables S8-S10).

Association between plasma PUFAs and incidence of GI cancers in different subgroups

The analysis revealed significant demographic disparities in GI cancer risk. Among individuals aged >55 years, a pronounced protective effect was observed (HR =0.73, 95% CI: 0.65–0.82, P<0.001), while no association was found for those ≤55 years (P for interaction =0.025). Sex-stratified analyses demonstrated contrasting risks: females exhibited elevated risk (HR =1.25, 95% CI: 1.06–1.47, P=0.007), whereas males showed reduced risk (HR =0.74, 95% CI: 0.65–0.86, P<0.001; P for interaction <0.001). Overweight (BMI 25–30 kg/m²) and obese (BMI >30 kg/m²) individuals also experienced lower risks (HR =0.81 and 0.82, respectively; P≤0.032), with no significant interaction by BMI category (P=0.16) (Figure 2).

Figure 2 Association between plasma PUFAs and incidence of gastrointestinal cancers in different subgroups. BMI, body mass index; CI, confidence interval; HR, hazard ratio; PUFA, polyunsaturated fatty acid.

For other cancers, notable findings included sex-driven risk variations in esophageal (higher in females, P<0.001) and CRCs (higher in females, P<0.001) (Figures S1,S2), age-related protection in CRC (>55 years, P<0.001) (Figure S2), and BMI-associated risk reduction in liver cancer (BMI >30 kg/m², P=0.003) (Figure S3). Gastric, bile duct and pancreatic cancers showed no statistically significant associations (Figures S4-S6). These results underscore the critical role of age, sex, and BMI in modulating GI cancer risk, with distinct patterns across subtypes.

Sensitivity analyses were conducted to assess the robustness of our findings. Across all these sensitivity analyses, the associations remained consistent (Tables S11-S15). In the site-specific analysis, no significant heterogeneity in the association was observed between patients with colon cancer and rectal cancer (Table S16).

Discussion

This large prospective cohort study, leveraging objective NMR-based measurements of plasma FAs in 91,239 UK Biobank participants, provides robust epidemiological evidence on the associations between circulating FAs and GI cancer risk. Over a median follow-up of 12.3 years, we observed that higher plasma PUFA levels were significantly associated with a reduced risk of overall GI cancer incidence, with a 21% lower risk per SD increase. Notably, these inverse associations were particularly pronounced for esophageal, colorectal, and liver cancers. Conversely, SFAs exhibited a positive association with GI cancer risk. Subgroup analyses further revealed that the protective effects of PUFAs were more substantial in males, older adults, and individuals with elevated BMI. These findings underscore the potential role of PUFA metabolism in GI cancer prevention and highlight the contrasting implications of different FA subtypes. These results align with emerging evidence on the role of PUFAs in modulating inflammatory pathways, lipid metabolism, and cellular signaling, which may collectively contribute to cancer prevention (22-24).

Our findings on the inverse association between plasma PUFAs and GI cancer risk align with emerging evidence on lipid metabolic reprogramming in carcinogenesis, yet reveal notable site-specific variations. The robust protective effect observed for esophageal cancer resonates with experimental data indicating that PUFAs, modulate inflammation and membrane signaling pathways implicated in esophageal carcinogenesis (25). The inverse relationship between PUFAs and CRC risk corroborates recent meta-analyses of prospective cohorts. For instance, a 2025 systematic review of 20 prospective studies reported that tissue biomarkers of total PUFAs and omega-3 PUFAs specifically were associated with reduced CRC risk, though dietary omega-6 PUFA intake showed mixed effects (26,27).

Notably, the lack of association between PUFAs and gastric cancer in our study contrasts with lipidomics research identifying specific plasma lipids as biomarkers for gastric lesion progression. This discrepancy may arise from methodological differences: targeted lipidomics in gastric studies quantified individual lipid species (28), whereas our NMR-based approach measured broad PUFA classes. Additionally, gastric cancer heterogeneity and H. pylori status, may obscure PUFA associations, as suggested by proteomic links between lipid transport proteins and gastric cancer risk. The positive association between SFAs and overall GI cancer risk further reinforces experimental evidence that SFAs promote tumor proliferation via upregulation of de novo lipogenesis enzymes and confer chemoresistance through membrane fluidity alterations (25).

Subgroup analyses revealing stronger PUFA protection in males, older adults, and high-BMI individuals suggest hormonal and metabolic contextual dependencies. While no prior studies examined PUFA interactions by sex in GI cancers, male-predominant upper GI cancers have been linked to androgen-related factors (29). Additionally, sex differences in PUFA metabolism may modulate tissue-specific bioavailability. These hypotheses are supported by experimental studies demonstrating estrogen-dependent regulation of PUFA elongation enzymes (22,30). The heightened effect in high-BMI subjects may reflect compensatory mechanisms, where PUFAs counteract obesity-induced inflammation and dysregulated lipid storage, a hypothesis warranting investigation into adipokine-PUFA crosstalk. The age-dependent protection aligns with evidence that aging exacerbates oxidative stress and mitochondrial dysfunction, processes mitigated by PUFA-derived resolvins (24). Conversely, the lack of association in younger individuals may reflect shorter exposure durations or competing lifestyle factors that dominate risk profiles in this group.

PUFAs, are precursors to bioactive lipid mediators that suppress pro-inflammatory cytokines such as TNF-α and interleukin-6 (IL-6), thereby attenuating chronic inflammation-a known driver of carcinogenesis (31,32). Experimental studies suggest that PUFAs inhibit the proliferation of cancer cells by downregulating the PI3K/Akt/mTOR pathway and inducing apoptosis through mitochondrial dysfunction (23,24). This anti-inflammatory mechanism is critical in GI cancers, where chronic inflammation drives carcinogenesis, particularly in colorectal and esophageal malignancies. The stronger association in older adults may reflect cumulative exposure to inflammatory insults, amplifying the protective role of PUFAs in this subgroup.

The divergent results for SFAs (positive association) versus PUFAs (inverse association) emphasize the importance of FA composition in cancer risk. SFAs promote membrane rigidity and activate TLR4/MyD88 signaling, fostering pro-tumorigenic inflammation. In contrast, PUFAs enhance membrane fluidity and promote anti-inflammatory mediator synthesis (33,34). These findings corroborate prior cohort studies but extend them by utilizing plasma biomarkers—a strength reducing dietary recall bias.

Our findings underscore two clinically actionable pathways to translate FA biology into cancer prevention strategies. First, plasma metabolomic signatures offer promise for precision risk stratification, exemplified by a 17-metabolite panel achieving robust diagnostic accuracy for CRC (35), suggesting utility for GI cancer screening. Second, targeted dietary interventions show mechanistic efficacy: replacing saturated fats with plant-based PUFAs preserves anti-tumor immunity in obesity (36), and combining probiotics with PUFAs synergistically increases tumor suppression by 40% through microbiota-mediated pathways (35). These approaches bridge molecular insights with feasible clinical applications.

While this study benefits from objective PUFA measurements and a large sample size, residual confounding by unmeasured factors cannot be excluded. The paradoxical female risk elevation requires validation, as residual confounding by hormone replacement therapy or reproductive factors may contribute. Additionally, the observational design precludes causal inference; Mendelian randomization studies are needed to clarify causality (37). Future research should integrate multi-omics approaches (like metabolomics, gut microbiome profiling) to elucidate how PUFA-gene-environment interactions modulate site-specific cancer risk.

Conclusions

In conclusion, our study provides robust epidemiological evidence that higher plasma PUFA levels are associated with a reduced risk of GI cancers, likely mediated through anti-inflammatory, metabolic, and microbiota-related mechanisms. These findings underscore the importance of dietary interventions targeting PUFA intake as a public health strategy for cancer prevention. Further randomized trials are needed to validate causality and optimize therapeutic applications of PUFAs in high-risk populations.

Acknowledgments

We would like to thank the UK Biobank for providing the public data.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2763/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2763/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2763/prf

Funding: This work was supported by the National Natural Science Foundation of China under grant No. 82272954 (to Y.W.), National Key R&D Program of China under grant No. 2019YFC0118802 (to J.W.), and Zhejiang Public Welfare Technology Research Project under grant No. 2023C03053 (to J.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2763/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Access to the data was granted by UK Biobank application number 91734. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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