Rohit Thakur, Mai Xu, Alexandra M Thornock, Joshuah Yon, Samuel Anyaso-Samuel, Martin Lauss, Thomas Rehling, Linh Bui-Raborn, Hayley Sowards, Gerard Duncan, Lea Jessop, Timothy Myers, Raj Chari, Erping Long, Karen Funderburk, Jinhu Yin, Rebecca Hennessey, Emory Hseih, Hannah Levin, Mitchell J Machiela, Tongwu Zhang, Göran Jönsson, D Timothy Bishop, Julia Newton-Bishop, Jeremie Nsengimana, Mark M Iles, Maria Teresa Landi, Matthew H Law, Thorkell Andresson, Jiyeon Choi, Leonard I Zon, Jianxin Shi, Melanoma Meta-Analysis Consortium, Kevin M Brown
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 risk genes with opposite associations with risk: higher levels of Rap guanine nucleotide exchange factor 1 (RAPGEF1) and lower levels of uridine-cytidine kinase 1 (UCK1). Colocalization analyses and conditional transcriptome-wide association studies (TWASs) suggest multiple causal cis-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 RAPGEF1 and UCK1 promoters. Focusing on RAPGEF1, we demonstrate that RAPGEF1 expression promotes melanocyte growth and drives colony formation of human immortalized melanocytes. Following treatment with human epidermal growth factor (EGF), RAPGEF1 overexpression activated both RAP1 and RAS. Further, we show that RAPGEF1 expression is significantly enriched in melanomas that lack strongly activating RAS-MAPK pathway mutations, which suggests that RAPGEF1 may promote oncogenic RAS-MAPK pathway signaling in melanomas. Furthermore, in these tumors, we provide preliminary evidence to support the prognostic relevance of RAPGEF1 expression in individuals whose melanomas lack RAS or BRAF 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.