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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.

frontiers in medicine

DNA Repair and Immune Response Pathways Are Deregulated in Melanocyte-Keratinocyte Co-cultures Derived From the Healthy Skin of Familial Melanoma Patients