DNA Repair and Immune Response Pathways Are Deregulated in Melanocyte-Keratinocyte Co-cultures Derived From the Healthy Skin of Familial Melanoma Patients
Year: 2021
Type: article
Study design: Observational Study
Abstract: Familial melanoma accounts for 10% of cases, being CDKN2A the main high-risk gene. However, the mechanisms underlying melanomagenesis in these cases remain poorly understood. Our aim was to analyze the transcriptome of melanocyte-keratinocyte co-cultures derived from healthy skin from familial melanoma patients vs. controls, to unveil pathways involved in melanoma development in at-risk individuals. Accordingly, primary melanocyte-keratinocyte co-cultures were established from the healthy skin biopsies of 16 unrelated familial melanoma patients (8 CDKN2A mutant, 8 CDKN2A wild-type) and 7 healthy controls. Whole transcriptome was captured using the SurePrint G3 Human Microarray. Transcriptome analyses included: differential gene expression, functional enrichment, and protein-protein interaction (PPI) networks. We identified a gene profile associated with familial melanoma independently of CDKN2A germline status. Functional enrichment analysis of this profile showed a downregulation of pathways related to DNA repair and immune response in familial melanoma (P < 0.05). In addition, the PPI network analysis revealed a network that consisted of double-stranded DNA repair genes (including BRCA1, BRCA2, BRIP1, and FANCA), immune response genes, and regulation of chromosome segregation. The hub gene was BRCA1. In conclusion, the constitutive deregulation of BRCA1 pathway genes and the immune response in healthy skin could be a mechanism related to melanoma risk.
Source: Frontiers in Medicine
Institutions: Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases, Hospital Clínic de Barcelona, Universitat de Barcelona, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Carlos III de Madrid, Universidad de Oviedo, Fernández-Vega Ophthalmological Institute, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,950
Funders: Fundació la Marató de TV3, Comunidad de Madrid, Centres de Recerca de Catalunya, European Commission, Radboud Universiteit, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Radboud Universitair Medisch Centrum, Universidad Carlos III de Madrid, National Institutes of Health, Seventh Framework Programme, Sixth Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, National Cancer Institute, Direcció General de Recerca, Generalitat de Catalunya
Awards: G1688618065, G168893872, G2015704975, G2291472998, G2719370042, G3022609761, G3309013542, Evaluación de las alteraciones inmunológicas subyacentes en el desarrollo, progresión y respuesta a las terapias inmunológicas en melanoma. Implicación de la microbiota en la inducción de tolerancia y efectos secundarios de las terapias inmunológicas, G373542579, G390724116, G41579285, G4418009050, G450706765, G4742044930, G478812525, G513475481, Genetic Epidemiology of Melanoma (GenoMel), Identificación de factores genéticos en individuos con nevus melanocíticos y su influencia en la determinación de la mutación BRAF(V600E) en plasma, G7598744334
OpenAlex ID: W3202390785