Evidence map›Paper›PMID 42716012›Full record

ArticleAmerican journal of human genetics2026

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

Rohit Thakur, Mai Xu, Alexandra M Thornock, Joshuah Yon, Samuel Anyaso-Samuel, Martin Lauss, Thomas Rehling, Linh Bui-Raborn, Hayley Sowards, Gerard Duncan and 24 more

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Article in American journal of human genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

34 authors.

Rohit ThakurLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Mai XuLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Alexandra M ThornockStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Boston, MA, USA; Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA.
Joshuah YonLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Samuel Anyaso-SamuelBiostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Martin LaussDivision of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185 Lund, Sweden; Lund University Cancer Center, 22185 Lund, Sweden.
Thomas RehlingLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Linh Bui-RabornLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Hayley SowardsLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Gerard DuncanProtein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
Lea JessopLaboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Timothy MyersLaboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Raj ChariGenome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Erping LongLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China.
Karen FunderburkLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Jinhu YinLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Rebecca HennesseyLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Emory HsiehLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Hannah LevinLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Mitchell J MachielaIntegrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Tongwu ZhangIntegrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Göran JönssonDivision of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185 Lund, Sweden; Lund University Cancer Center, 22185 Lund, Sweden.
D Timothy BishopLeeds Institute for Data Analytics, University of Leeds, Leeds, UK.
Julia Newton-BishopLeeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, UK.
Jeremie NsengimanaPopulation Health Sciences Institute, Faculty of Medical Sciences, Newcastle University and NIHR Biomedical Research Centre, Newcastle Upon Tyne, UK.
Mark M IlesLeeds Institute for Data Analytics, University of Leeds, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Maria Teresa LandiIntegrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Matthew H LawPopulation Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia; School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.
Thorkell AndressonProtein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
Jiyeon ChoiLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Leonard I ZonStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Boston, MA, USA; Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
Jianxin ShiBiostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Melanoma Meta-Analysis Consortium
Kevin M BrownLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: kevin.brown3@nih.gov.

Funding

Genetic Epidermiology of MelanomaR01CA083115 · NCI · UNIVERSITY OF PENNSYLVANIA · PI BISHOP, DAVID TIMOTHY, ELDER, DAVID ERIC · 2001 to 2017
$13.0M
Intramural NIH HHS Z99 CA999999NCI NIH HHS R01 CA083115
6 · The paper itself

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.

Indexed as

Genetic Predisposition to DiseaseGuanine Nucleotide Exchange FactorsGuanine Nucleotide-Releasing Factor 2MelanomaNevusras ProteinsGene Expression Regulation, NeoplasticGenome-Wide Association StudyHumansMelanocytesrap1 GTP-Binding ProteinsGuanine Nucleotide Exchange FactorsGuanine Nucleotide-Releasing Factor 2rap1 GTP-Binding Proteinsras Proteinscapture-HiCGWASmelanomaRAPRAS

Identifiers

PMID42716012
PMCPMC13641683

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.