Multiomic Sequencing of Intermediate- to High-Risk Cutaneous Squamous Cell Carcinoma Identifies Critical Genes and...

Cutaneous squamous cell carcinoma is one of the most common cancers in humans and kills as many people annually as melanoma. The understanding of the transcriptional changes with respect to high-risk clinical/histopathologic features and outcome is poor. In this study, we examine stage-matched, outcome-differentiated cutaneous squamous cell carcinoma using whole-exome and transcriptome sequencing. Exome analysis identified key driver mutations, including TP53, CDKN2A, NOTCH1, SHC4, MIIP, CNOT1, C17orf66, LPHN2, and TTC16, and pathway enrichment of driver mutations in replicative senescence, cellular response to UV, cell-cell adhesion, and cell cycle. Transcriptomic analysis identified pathway enrichment of immune signaling/inflammation, cell-cycle pathways, extracellular matrix function, and chromatin function. Integrative analysis identified 183 critical genes in carcinogenesis and were used to develop a gene expression panel for outcome. Three outcome-related gene clusters included those involved in keratinization, cell division, and metabolism. We found 16 genes whose expressions may be associated with metastasis (risk score ≥ 9 Met and risk score < 9 NoMet) with an area under the curve of 97.1%, sensitivity of 95.5%, specificity of 85.7%, and overall accuracy of 90%. Eleven genes were chosen to generate the risk score for overall survival, with an overall survival prediction of 80.8% and each risk gene increasing the risk of death by 2.47 (hazard ratio = 2.47, P < .001).