Polyunsaturated Fatty Acids and Skin Cancer: Two-Sample Mendelian Randomization Study

Area of Science:

• Genetics
• Metabolism
• Oncology

Background:

• Observational studies suggest links between dietary polyunsaturated fatty acids (PUFAs) and cancer risk.
• Causal inference for skin cancer is limited by recall bias, confounding, and reverse causation.

Purpose of the Study:

• To evaluate the causal association between genetically predicted circulating PUFA levels and the risk of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma.
• To investigate the role of endogenous PUFA metabolism in skin carcinogenesis.

Main Methods:

• A 2-sample Mendelian randomization (MR) study utilizing UK Biobank and FinnGen consortium GWAS summary statistics.
• Genetic instruments derived for omega-3, docosahexaenoic acid, omega-6, linoleic acid, and the omega-6:3 ratio.
• Multiple MR methods applied to ensure robustness and assess pleiotropy.

Main Results:

• Higher genetically predicted linoleic acid to total fatty acid ratio associated with lower BCC and SCC risk.
• Higher genetically proxied serum omega-3 levels associated with increased risk of BCC, SCC, and melanoma.
• FADS1 gene variant rs174528 influenced SCC risk, indicating a role for endogenous PUFA metabolism.

Conclusions:

• This MR analysis supports a causal role for circulating PUFAs in skin cancer development.
• Highlights the importance of FADS-mediated endogenous PUFA metabolism in skin carcinogenesis.
• Provides novel insights into genetic and metabolic factors influencing skin cancer susceptibility.