Genetic background shapes skin cancer risk in patients with autoimmune hypothyroidism

Hypothyroidism has been associated with increased skin cancer risk, whereas greater genetic susceptibility to hypothyroidism is associated with lower risk. These opposing associations suggest that the average risk associated with hypothyroidism may conceal substantial heterogeneity among patients, and that genetic background could help identify those at highest risk. In this study, we analyzed more than 650,000 individuals across All of Us and FinnGen cohorts to determine whether a hypothyroidism polygenic risk score (H-PRS) stratifies skin cancer risk among patients with autoimmune hypothyroidism and whether integration of a skin cancer polygenic risk score (SC-PRS) further refines risk. In FinnGen, autoimmune hypothyroidism was associated with increased skin cancer hazard (hazard ratio [HR] = 1.10; 95% CI [1.06, 1.15]), whereas H-PRS was inversely associated with risk (HR=0.97 per 1-SD increase; 95% CI [0.95, 0.98]). The hypothyroidism x H-PRS interaction was also negative (HR=0.94; 95% CI [0.91, 0.98]), indicating greater hypothyroidism-associated risk at lower H-PRS. The hypothyroidism and H-PRS associations replicated in All of Us, and similar H-PRS risk gradients were observed for melanoma, basal cell carcinoma, and squamous cell carcinoma in both cohorts. Among hypothyroid patients, predicted 10-year risk increased with higher SC-PRS and lower H-PRS. Combined clinical-genetic profiles had HRs ranging from 2.32 at the 20th H-PRS/80th SC-PRS percentiles to 3.37 at the 5th/95th percentiles, exceeding published point estimates for the established dermatological risk factors. Among women aged 55, representing the more commonly affected sex at approximately the median age of diagnosis, 10-year risk of skin cancer was 14.9% (95% CI [8.4%, 20.9%]) in the highest-SC-PRS/lowest-H-PRS quartiles versus 2.8% (95% CI [1.0%, 4.7%]) in the opposite quartiles. Overall, these findings support PRS-guided risk stratification for targeted skin cancer prevention and surveillance.