Abstract

Genome-wide association studies identified a melanoma- and nevus count-associated locus on chromosome band 9q34.13. Fine-mapping and melanocyte expression data collectively suggest two potential causal genes with opposite association with risk: higher levels of Rap guanine nucleotide exchange factor 1 () and lower levels of uridine-cytidine kinase 1 (). Colocalization analyses and conditional TWAS suggest multiple causal -regulatory sequence variants in partial linkage disequilibrium (LD) to each other. Melanocyte capture-HiC and CRISPR-inhibition demonstrated regulatory interactions between fine-mapped variants and the and promoters. Focusing on , we demonstrate expression promotes melanocyte growth and drives malignant transformation of human immortalized melanocytes. Following treatment with human EGF, overexpression activated both RAP1 and RAS. Further, we show expression is significantly enriched in melanomas lacking strongly activating RAS-MAPK mutations, suggesting that may promote oncogenic RAS-MAPK signaling in melanomas. Furthermore, in these tumors, we provide preliminary evidence to support the prognostic relevance of expression in patients lacking or mutations. Together with other recent studies, these data suggest that germline variation influencing RAS activation may play a key role in nevus development and melanoma risk.