Analysis of the TCGA Dataset Reveals that Subsites of Laryngeal Squamous Cell Carcinoma Are Molecularly Distinct

SIMPLE SUMMARY: Squamous cell carcinomas from different parts of the larynx have distinct presentations and prognoses, but the molecular basis for this discrepancy has yet to be characterized. We aimed to determine whether different types of mutations at the DNA, mRNA, and protein levels exist to explain the differential prognoses observed. We found that cancers of the supraglottis had higher overall and smoking-associated genome mutations. Further, supraglottic cancers had a significantly poorer prognosis when other clinical variables and mutational status were controlled for. Different protein pathways were enriched in each subsite: muscle-related in the glottis and neural in the supraglottis. Specific cancer-related proteins were also differentially abundant between the supraglottis and glottis. Our findings may partially explain therapeutic response differences, but further study is required for validation. ABSTRACT: Laryngeal squamous cell carcinoma (LSCC) from different subsites have distinct presentations and prognosis. In this study, we carried out a multiomic comparison of LSCC subsites. The Cancer Genome Atlas (TCGA) LSCC cohort was analyzed in the R statistical environment for differences between supraglottic and glottic cancers in single nucleotide variations (SNVs), copy number alterations (CNAs), mRNA abundance, protein abundance, pathway overrepresentation, tumor microenvironment (TME), hypoxia status, and patient outcome. Supraglottic cancers had significantly higher overall and smoking-associated SNV mutational load. Pathway analysis revealed upregulation of muscle related pathways in glottic cancer and neural pathways in supraglottic cancer. Proteins involved in cancer relevant signaling pathways including PI3K/Akt/mTOR, the cell cycle, and PDL1 were differentially abundant between subsites. Glottic and supraglottic tumors have different molecular profiles, which may partially account for differences in presentation and response to therapy.