Polyunsaturated Fatty Acids and Skin Cancer: Two-Sample Mendelian Randomization Study
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Background: Observational studies have suggested associations between dietary polyunsat- urated fatty acids (PUFAs) and cancer risk; however, causal inference regarding skin cancer remains limited due to potential recall bias, confounding, and reverse causation. Objective: This study aimed to evaluate the causal association between genetically predicted circulating PUFA levels and the risk of skin cancers, including basal cell carcinoma (BCC), squa- mous cell carcinoma (SCC), and melanoma. Methods: We conducted a 2-sample Mendelian randomization (MR) study using genome-wide association study summary statistics from the UK Biobank (PUFAs, n=115,006) and the FinnGen consortium (BCC, n=26,272; SCC, n=4,663; melanoma, n=5,753). Genetic instruments were derived for omega-3, docosahexaenoic acid, omega-6, linoleic acid, and the omega-6:3 ratio. Multiple MR methods—including inverse-variance weighted, MR-Egger, weighted median, weighted mode, and MR-PRESSO—were applied to test for consistency and assess pleiotropy and heterogeneity. Results: A higher genetically predicted linoleic acid to total fatty acid ratio was associated with a significantly lower risk of BCC and SCC. Conversely, higher genetically proxied serum omega-3 levels were associated with increased risks of BCC, SCC, and melanoma. The risk effect on SCC was attenuated upon exclusion of rs174528, a variant in the fatty acid desaturase 1 (FADS1 ) gene, suggesting a role for endogenous PUFA metabolism in carcinogenesis. Conclusion: This MR analysis supports a causal role of circulating PUFAs in skin cancer devel- opment and highlights the importance of FADS-mediated endogenous PUFA metabolism. These findings provide novel insights into the genetic and metabolic underpinnings of skin cancer susceptibility.
Abstract
Background: Observational studies have suggested associations between dietary polyunsat- urated fatty acids (PUFAs) and cancer risk; however, causal inference regarding skin cancer remains limited due to potential recall bias, confounding, and reverse causation. Objective: This study aimed to evaluate the causal association between genetically predicted circulating PUFA levels and the risk of skin cancers, including basal cell carcinoma (BCC), squa- mous cell carcinoma (SCC), and melanoma. Methods: We conducted a 2-sample Mendelian randomization (MR) study using genome-wide association study summary statistics from the UK Biobank (PUFAs, n=115,006) and the FinnGen consortium (BCC, n=26,272; SCC, n=4,663; melanoma, n=5,753). Genetic instruments were derived for omega-3, docosahexaenoic acid, omega-6, linoleic acid, and the omega-6:3 ratio. Multiple MR methods—including inverse-variance weighted, MR-Egger, weighted median, weighted mode, and MR-PRESSO—were applied to test for consistency and assess pleiotropy and heterogeneity. Results: A higher genetically predicted linoleic acid to total fatty acid ratio was associated with a significantly lower risk of BCC and SCC. Conversely, higher genetically proxied serum omega-3 levels were associated with increased risks of BCC, SCC, and melanoma. The risk effect on SCC was attenuated upon exclusion of rs174528, a variant in the fatty acid desaturase 1 (FADS1 ) gene, suggesting a role for endogenous PUFA metabolism in carcinogenesis. Conclusion: This MR analysis supports a causal role of circulating PUFAs in skin cancer devel- opment and highlights the importance of FADS-mediated endogenous PUFA metabolism. These findings provide novel insights into the genetic and metabolic underpinnings of skin cancer susceptibility.