Book Description

Despite the genetic bases of many rare skin diseases having been elucidated in the past years, the mutations in the causal genes often fail to explain on their own the vast array of phenotypic manifestations in these pathologies. Recessive Dystrophic Epidermolysis Bullosa (RDEB), Kindler syndrome (KS) and Xeroderma Pigmentosum C (XPC) are three genodermatoses that share a number of features, including a predisposition to cancer, whose mechanisms are not yet fully understood. In this study we have investigated the transcriptional signature across these conditions to address the role of dermal environment in the development of the pathology. Fibroblasts isolated from several RDEB, XPC and KS patients, as well as healthy donors, have been studied using RNA-Seq technology. The analysis included a thorough examination of the differentially expressed genes, a functional enrichment analysis and the determination of the affected signaling circuits using computational models of signaling pathway activity. The results revealed a set of 227 genes and 42 signaling circuits commonly altered in all three conditions, along with unique mechanisms acting in each of them. The common signaling circuits and biomarkers uncovered by the analysis point towards a phenotype in which the fibroblasts of these conditions show similarities to cancer-associated fibroblasts, enabling a favorable environment for tumor development and progression. We anticipate this approach, focused on the mechanisms that govern cell behavior, to be useful in explaining obscure phenotypic traits of these genodermatoses and to increase the number of targets for effective therapeutic intervention.