Disentangling the Complex Relationships Between Autoimmune Diseases and Cancer Through Polygenic Risk Scores: Evidence from a Large Prospective Study

Although prior studies have reported a link between autoimmunity and carcinogenesis, the roles of genetic factors and potential mediators involved in this process remain elusive. We constructed disease-specific and combined polygenic risk scores (PRSs) for 6 common autoimmune diseases (AIDs) (systemic lupus erythematosus [SLE], rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis [UC], and type 1 diabetes mellitus [T1D]) in the UK Biobank cohort. Compared to those without AID, AID patients at baseline had increased risks of overall cancer, hematological, digestive, and urinary cancer. The combined AID-PRS was significantly associated with increased risks of hematological cancer (HR [95% CI] per SD increase: 1.06 [1.03–1.09]) and non-Hodgkin's lymphoma (HR [95% CI] per SD increase: 1.10 [1.05–1.14]). For individual AID-PRSs, we identified 21 significant associations between 5 PRSs and 11 types of cancer in the overall population, along with 15 additional associations in the sex-stratified analysis. For example, SLE-, UC-, and T1D-PRS showed complex cross-cancer effects on risks of up to 6 cancer types. These associations were generally independent of immunosuppressant drug use. Differential associations of SLE-PRS with prostate cancer risk were found by prostate cancer PRS status ( P _interaction <0.05). Several peripheral biomarkers, including red or white blood cell counts, platelet counts, and CRP partly mediated the PRS associations (up to 16.96%). Our study provides important insights into the role of autoimmune diseases in carcinogenesis, which also highlights opportunities for target cancer screening and prevention in potentially vulnerable populations.