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

Abstract 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.