Simple SummarySolid organ transplant recipients are at increased risk for keratinocyte cancer of the skin. In our study, we carefully matched our cases and controls for major risk factors of keratinocyte cancer such as age, sex, transplanted organ, post-transplant period, immunosuppressive therapy, and UV exposure. In addition, they also had comparable cumulative UV exposure. Using this approach, we identified several genetic loci involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV associated with the occurrence of multiple keratinocyte cancers.AbstractBecause of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (n= 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte cancers. We found one genome-wide significant association of a common single nucleotide polymorphism located inEXOC3(rs72698504). In addition, we found several variants with ap-value of less than 10−5associated with the number of keratinocyte cancers. These variants were located in the genesCYB561,WASHC1,PITRM1-AS1,MUC8,ABI3BP,andTHBS2-AS1. Using whole exome sequencing data, we performed groupwise tests for rare missense variants in our dataset and found robust associations (p< 10−6, Burden Zeggini test) betweenMC1R,EPHA8,EPO,MYCT1,ADGRG3, andMGME1and keratinocyte cancer. Thus, overall, we detected genes involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV as genetic risk factors for multiple keratinocyte cancers in solid organ transplant recipients. We also grouped selected genes to pathways and found a selection of genes involved in the “cellular response to UV” to be significantly associated with multiple keratinocyte cancers.