Background: Cutaneous squamous cell carcinoma (cSCC) is the second most frequent non-melanoma skin cancer, with a 10-year survival rate >90% after surgical resection. However, recurrence and nodal/visceral metastasis can significantly affect survival and outcomes. In particular, poorly differentiated (G3) cSCC is associated with a higher risk of recurrence. To date, precise patient risk- prognostication needs to reach in clinical practice. The aim of this study was to understanding the molecular events characterizing G3-cSCC progression.Methods: From a retrospective series of patients with G3-cSCC diagnosed at the Turin University Hospital (2016-2021) (1), a subgroup of 48 cases were analyzed by performing a transcriptomic analysis using the nCounter® PanCancer Progression Panel (NanoString Technologies, Seattle, WA, USA). Specifically, 16 progressed G3-cSCC (cutaneous/lymph node/visceral progression), 16 G3-cSCC-LR (non-progressed, negative margins, absence of vascular/perineural invasion and desmoplasia, Breslow thickness ≤6 mm, no immunosuppression, and a follow-up >30 months) and 16 G3-cSCC-HR (non-progressed, negative margins, presence of at least one of the aforementioned parameters, follow-up >30 months) were enrolled.Results: 21 upregulated genes, including COL1A1, COL1A2, COL5A2, COL3A1, SERPINH1, PLAUR, and CCL11 (p<0.05) and 6 downregulated genes, including PROM1 (p<0.05) were identified comparing progressed G3-cSCC with G3-cSCC-LR. Extracellular matrix remodeling, metabolic regulation, hypoxia, inflammatory signaling and angiogenesis were the most differentially involved pathways between the two groups. Otherwise, comparing G3-cSCC-LR and G3-cSCC-HR hypoxia and angiogenesis pathways were observed. In this comparison, 5 upregulated (ARHG, CYBB, SH2B3, GIMAP6, RAC2, p<0.05) and 4 downregulated (GATA4, KDM1A, CHAD, ASPN, p<0.05) genes were revealed. No differentially expressed genes were detected, comparing progressed G3-cSCC and G3-cSCC-HR. However, pathway analysis highlighted differences in hypoxia signaling, angiogenesis, EMT to metastasis and extracellular matrix remodeling.Conclusions: Our analysis of mRNA provides a comprehensive evaluation of the pathways that promote recurrence and progression in G3-SCC. These observations may represent a starting point in identifying biomarkers useful in the prognostic stratification of this high-risk subgroup of cSCC.References:1 Roccuzzo G, Orlando G, Rumore MR, et al. Predictors of Recurrence and Progression in Poorly Differentiated Cutaneous Squamous Cell Carcinomas: Insights from a Real-Life Experience. Dermatology. 2024;240(2):329-336.
Italian Melanoma Intergroup (Thu,) studied this question.