Polygenic prediction of actinic keratosis identifies transplant recipients at risk of extreme lesion burden.

Transplant recipients have an elevated risk of actinic keratosis (AK), a precursor of squamous cell carcinoma. We assessed whether an AK polygenic risk score (PRS) can identify transplant-naive individuals and transplant recipients at risk of multiple AKs who may benefit from early prevention. Using genome-wide association data (140 339 cases; 1 430 776 controls), we developed an AK PRS and evaluated it in cohort studies of European descent individuals in the QSkin Sun and Health Study (QSkin) (N = 12 843), Skin Tumors in Allograft Recipients Study (STAR) (N = 357), UK Biobank (N = 963), and All of Us (N = 1859). The PRS was strongly associated with higher AK burden in transplant-naive individuals, conferring a 5-fold increased risk of developing ≥20 AKs (odds ratio [OR] per standard deviation [SD] increase in the PRS = 5.06, 95% confidence interval [CI] = 4.69-5.46). In transplant recipients, it was associated with up to a 2.5-fold increased risk of developing ≥1 AK (United Kingdom Biobank [UKB] OR per SD = 2.49, 95% CI = 1.91-3.23; STAR OR per SD = 1.79, 95% CI = 1.10-2.91; All of Us OR per SD = 1.52, 95% CI = 1.35-1.70). The PRS improved prediction of ≥20 AKs by 13% beyond age and sex (AUC 0.90 vs 0.77) and identified the highest-risk 20% with a 9-fold increased risk in transplant-naive individuals (OR = 8.61, 95% CI = 7.26-10.22) and a 2-fold increased risk in transplant recipients (OR = 2.23, 95% CI = 1.26-4.20), compared to the middle-risk 60%. Incorporating PRS into pretransplant and posttransplant care could enable earlier, personalized prevention.