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Functional characterization of the 9q34.13 locus identifies RAPGEF1 as a candidate gene modulating risk for melanoma and nevi via RAS activation

Lookup NU author(s): Dr Jérémie NsengimanaORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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 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.

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Author(s): Thakur T, Mai Xu M, Thornock AM, Yon J, Anyaso-Samuel S, Lauss M, Rehling T, Bui-Raborn L, Sowards H, Duncan G, Jessop L, Myers T, Chari R, Long E, Funderburk K, Yin J, Hennessey R, Hseih E, Levin H, Machiela MJ, Zhang T, Jönsson G, Bishop DT, Newton-Bishop J, Nsengimana J, Iles MM, Landi MT, Law MH, Anderson T, Choi J, Zon LI, Shi J, Brown KM

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2026

Pages: epub ahead of print

Online publication date: 09/09/2026

Acceptance date: 18/08/2026

Date deposited: 10/09/2026

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: https://doi.org/10.1016/j.ajhg.2026.08.014

DOI: 10.1016/j.ajhg.2026.08.014

ePrints DOI: 10.57711/08ye-cr22

Data Access Statement: The small RNA sequencing data supporting the current study have not been deposited in a public repository because they are being used in an ongoing larger miRNA eQTL study. These data are available from the corresponding author upon reasonable request.

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