Oral cancer is a significant global health concern, with a rising incidence, particularly in developing nations. While established risk factors include age, sex, smoking, alcohol consumption, HPV infection, and betel nut use, a substantial portion (approximately 50%) of oral cancer cases remain unexplained by these factors. This has prompted research into other potential etiological contributors, including the role of lipid metabolism and fatty acids in carcinogenesis. Erythrocyte membrane fatty acids serve as stable biomarkers reflecting medium-to-long-term exposure, offering advantages over serum or plasma fatty acid measurements. The composition of erythrocyte membrane fatty acids is influenced by both dietary intake and metabolism, encompassing saturated, monounsaturated, trans-unsaturated, and polyunsaturated fatty acids (ω-3 and ω-6 families). Among these, ω-3 PUFAs, including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and the ω-3 index (EPA + DHA), have garnered considerable research interest. Reduced erythrocyte ω-3 PUFAs have been linked to increased risks of coronary heart disease and neuropsychiatric disorders. Emerging evidence suggests an association between dietary or blood ω-3 PUFAs and various cancers, including head and neck cancer (HNC), esophageal cancer, colorectal cancer, and breast cancer, largely independent of known risk factors. However, the association between ω-3 PUFAs and oral cancer remains largely unexplored. This case-control study aimed to (1) assess the association between erythrocyte ω-3 PUFAs and oral cancer risk and (2) evaluate potential interactions between erythrocyte ω-3 PUFAs and established risk factors such as smoking and drinking.

The literature on the relationship between ω-3 PUFAs and cancer risk presents a mixed picture. Some studies have reported inverse associations between blood ω-3 PUFAs and cancer risk, such as those linking α-linolenic acid and docosapentaenoic acid with reduced pancreatic cancer risk. A meta-analysis showed an inverse association between ω-3 PUFAs and colorectal cancer. Another meta-analysis found a significant inverse association between high serum DPA and total prostate cancer risk. However, other studies have found no association or even a positive association between plasma ω-3 PUFAs and cancer risk. For example, a case-cohort analysis found no association between plasma fatty acids and prostate cancer risk. Similarly, studies have shown no association or even a positive association between plasma phospholipid fatty acids (EPA, DPA, DHA) and gastric cancer risk and prostate cancer risk. The role of ω-3 PUFAs in oral cancer specifically has received limited attention, creating a gap in the literature that this study aims to address. Prior research on dietary ω-3 PUFAs and HNC has shown conflicting results; some studies show a protective effect. The effects of ω-3 PUFAs are further complicated by the possible interactions with other risk factors like smoking and alcohol consumption, making the investigation of this study important.

This hospital-based case-control study recruited participants from the First Affiliated Hospital of Fujian Medical University between September 2010 and January 2019. Cases included patients with histologically confirmed primary oral cancer, Chinese, residing in Fujian Province for at least 10 years, and aged 20–80 years. Patients with recurrent or metastatic cancer, or those who had undergone chemotherapy or radiotherapy were excluded. Controls were recruited from the hospital's health examination center, excluding individuals with a history of cancer. A total of 236 oral cancer patients and 300 controls were included. All participants provided informed consent, and the study protocol was approved by the Institutional Review Board of Fujian Medical University. Data on demographic characteristics were collected through face-to-face interviews. Approximately 5 mL of fasting blood was collected from each participant in an EDTA tube. Erythrocytes were separated by centrifugation. Erythrocyte membrane fatty acids were extracted and analyzed by gas chromatography. Four ω-3 PUFAs (ALA, EPA, DPA, DHA) were measured and expressed as percentages of total fatty acids. Total ω-3 PUFAs and the ω-3 index were calculated. Statistical analysis included χ² tests or Fisher's exact tests for categorical variables, t-tests or Wilcoxon rank-sum tests for continuous variables, restricted cubic splines to assess non-linear relationships, and logistic regression to calculate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Stratified analyses were performed to investigate interactions between ω-3 PUFAs and smoking and drinking status.

The study included 236 oral cancer patients and 300 controls. Cases were more likely to be male, smokers, drinkers, and have lower BMI compared to controls. Erythrocyte levels of ALA, EPA, DPA, DHA, total ω-3 PUFAs, and the ω-3 index were significantly lower in the oral cancer group compared to controls. Restricted cubic spline analysis revealed non-linear inverse relationships between these ω-3 PUFAs and oral cancer risk. Multivariate logistic regression analysis, adjusting for age, sex, education, BMI, occupation, oral hygiene, smoking, and drinking, showed statistically significant inverse associations between erythrocyte EPA, DHA, total ω-3 PUFAs, and ω-3 index and oral cancer risk. The adjusted ORs were 0.54 (95% CI: 0.37-0.79) for EPA, 0.19 (95% CI: 0.08-0.45) for DHA, 0.12 (95% CI: 0.04-0.32) for total ω-3 PUFAs, and 0.21 (95% CI: 0.09-0.47) for ω-3 index. Stratified analyses indicated significant interactions between ω-3 PUFAs and both smoking and drinking. The inverse association between EPA and oral cancer was significant only in non-smokers, while the inverse associations between ALA, EPA, and DHA were significant only in non-drinkers. These findings suggest a potential protective effect of ω-3 PUFAs against oral cancer, particularly in individuals who do not smoke or drink.

This study provides evidence of an inverse association between erythrocyte ω-3 PUFAs and oral cancer risk, supporting the potential protective role of these fatty acids. The non-linear relationship suggests a dose-response effect, with greater protection at higher levels of ω-3 PUFAs. The observed interactions with smoking and drinking highlight the complex interplay between lifestyle factors and dietary components in oral cancer etiology. The protective effect of ω-3 PUFAs may be more pronounced in non-smokers and non-drinkers, potentially due to the counteracting effects of smoking and alcohol on inflammation and oxidative stress. These findings align with some previous research on dietary ω-3 PUFAs and HNC, but contrast with other studies which found no or even positive associations with other cancer types. Further research is needed to explore the underlying mechanisms of the observed interactions and to investigate the potential for ω-3 PUFAs as a preventive or therapeutic strategy for oral cancer.

This case-control study demonstrated a significant inverse association between erythrocyte ω-3 PUFAs and oral cancer risk. The protective effect of ω-3 PUFAs appeared stronger in non-smokers and non-drinkers. These findings suggest a potential role for ω-3 PUFAs in oral cancer prevention. Future prospective studies with larger sample sizes and longer follow-up periods are needed to validate these findings and clarify the mechanisms involved. Further research should also focus on exploring the optimal levels of ω-3 PUFAs for cancer prevention and whether supplementation may offer protective benefits.

This study has several limitations. As a case-control study, it cannot establish causality and is susceptible to recall bias. Erythrocyte fatty acid levels may be influenced by changes in diet or behavior related to disease symptoms, introducing potential reverse causality. While several confounding factors were adjusted for, the lack of data on medications affecting fatty acid levels could introduce residual confounding. The relatively small sample size limits the generalizability of the findings. Further larger prospective studies are needed to confirm these findings and explore causal relationships.