Functional characterization of the 9q34.13 locus identifies RAPGEF1 as modulating risk for melanoma and nevi via RAS activation
Year: 2025
Type: preprint
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 ( RAPGEF1 ) and lower levels of uridine-cytidine kinase 1 ( UCK1 ). Colocalization analyses and conditional TWAS 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 RAPGEF1 expression promotes melanocyte growth and drives malignant transformation of human immortalized melanocytes. Following treatment with human EGF, RAPGEF1 overexpression activated both RAP1 and RAS. Further, we show RAPGEF1 expression is significantly enriched in melanomas lacking strongly activating RAS-MAPK mutations, suggesting that RAPGEF1 may promote oncogenic RAS-MAPK signaling in melanomas. Furthermore, in these tumors, we provide preliminary evidence to support the prognostic relevance of RAPGEF1 expression in patients lacking 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.
Authors: 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, Goran Jonsson, 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, Kevin M. Brown
Institutions: National Cancer Institute, Division of Cancer Epidemiology and Genetics, Boston Children's Hospital, Howard Hughes Medical Institute, Harvard University, Dana-Farber Cancer Institute, Lund University, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. (United States), Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, University of Michigan, University of Leeds, NIHR Newcastle Biomedical Research Centre, Newcastle University, Leeds Teaching Hospitals NHS Trust, Queensland University of Technology, The University of Queensland, QIMR Berghofer Medical Research Institute
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Health and Human Services, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, National Institutes of Health, HORIZON EUROPE Framework Programme, Leeds Biomedical Research Centre, National Cancer Institute
OpenAlex ID: W4417115232