Multi-omic analysis of cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa

Summary: Abstract Body: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare genodermatosis caused by loss-of-function mutations in COL7A1, encoding type VII collagen. RDEB is characterized by severe skin and mucosal blistering, often complicated by the development of life-threatening cutaneous squamous cell carcinoma (SCC), for which no curative treatment exists. To investigate the molecular pathways driving carcinogenesis in RDEB-SCC, we conducted a translational study (NCT04285294) involving 20 RDEB patients. Among them, 5 patients developed aggressive SCC (SCC-AG) with rapid recurrence and/or metastasis, while 15 patients had less aggressive SCC (SCC-NA) with prolonged survival. As controls, 17 individuals from the general population with UV-induced SCC (UV-SCC) were included. Bulk transcriptomic (Limma) and proteomic analyses identified 1810 differentially expressed genes (DEGs) and 114 differentially expressed proteins (DEPs) (fold change >1.5, adjusted p-value <0.05) between RDEB-SCC and UV-SCC, showed enrichment of cell junction, extracellular matrix organization (ECM) pathways, and complement activation cascade (Reactome). Comparative analysis of SCC-AG versus SCC-NA revealed 1124 DEGs and 110 DEPs, downregulation of immune response and ROS detoxification, upregulation of MET signaling and ECM pathways. Single-cell transcriptomic analysis (8 RDEB-SCC, 3 UV-SCC, 3 healthy control skin) revealed differences in cell-type proportions, enriched pathways within clusters (Reactome), and predicted cell-cell interactions (CellChat), identifying specific features of RDEB-SCC, including SCC-AG (n=1). Omic signatures were analyzed through the LINCS drug repurposing database (NIH), identifying 6 potential therapeutic candidates, including rigosertib, which will be tested on primary SCC-AG cells and spheroids. This work aims to advance novel therapeutic strategies for SCC in RDEB patients. Lucile Marchal¹, Sonia Gaucher¹, Kevin Roger², Francesco Carbone¹, Nicolas Cagnard¹, Maxime Battistella³, Emmanuelle Bourrat³, Chiara Guerrera², Alain Hovnanian^{1, 3}, Matthias Titeux¹, Hélène Ragot¹ 1. Institut Imagine Institut des Maladies Genetiques, Paris, France. 2. Institut Necker-Enfants Malades, Paris, France. 3. Hopital Saint-Louis, Paris, France. UV Biology/Injury and Non-melanoma Cancers