Targeted next-generation sequencing of matched localized and metastatic primary high-risk SCCs identifies driver and co-occurring mutations and novel therapeutic targets

Background: Cutaneous squamous cell carcinoma (SCC) is the second most common type of skin cancer and is responsible for over one million cases annually. While only 3–5 % of SCCs metastasize, those that do are associated with significant morbidity and mortality. Using gene mutations to help predict metastasis and select therapeutics is still being explored. Objective: To present novel data from targeted sequencing of 20 case-matched localized and metastatic high-risk SCCs. Methods: A cancer-associated gene panel of 76 genes was run from formalin-fixed paraffin-embedded samples of 20 case-matched localized (10) and metastatic (10) high-risk SCCs (Vela Diagnostics). Results: Using spatial clustering analysis, primary driver mutations were identified asEGFR in localized SCC and CDH1 in metastatic SCC. ERBB4 and STK11 were found to be significant co-occurring mutations in localized SCC. Pathway analyses showed the RTK/RAS, TP53, TGF-b, NOTCH1, PI3K, and cell cycle pathways to be highly relevant in all high-risk SCCs with the Wnt pathway enhanced in metastatic SCC only. Conclusions: This study compared gene mutations between localized and metastatic SCC with the intent of identifying key differences and new potential targeted treatment options. To our knowledge, the co-occurrence ofERBB4 and STK11 mutations has not been previously reported. Targeted inhibition of CDH1 and the Wnt pathway should be further explored in metastatic SCC.