Multi-omic Sequencing of Intermediate to High-Risk Cutaneous Squamous Cell Carcinoma Identifies Critical Genes and Expression Patterns Associated with Disease and Poor Outcomes

Cutaneous squamous cell carcinoma (cSCC) 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/histopathological features and outcome is poor. Here, we examine stage-matched, outcome-differentiated cSCC 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 (GEP) for outcome. Three outcome-related gene clusters included those involved in keratinization, cell division, and metabolism. We found 16 genes that may predict metastasis (risk score ≥ 9 Met & risk score < 9 NoMet) with an AUC of 97.1%, sensitivity 95.5%, specificity 85.7%, and overall accuracy of 90%. Eleven genes were chosen to generate the risk score for Overall Survival (OS) with an OS prediction of 80.8% and each risk gene increasing the risk of death by 2.47 (HR: 2.47; p<0.001).