Abstract
ObjectivesThis study aims to identify a robust signature that performs well in predicting overall survival across tumor phenotypes and treatment strata, and validates the application of Monte Carlo cross validation (MCCV) as a means of identifying molecular signatures when utilizing small and highly heterogeneous datasets. Materials and methodsRNA sequence gene expression data for 264 patient tumors were acquired from The Cancer Genome Atlas (TCGA). 100 iterations of Monte Carlo cross validation were applied to differential expression and Cox model validation. The association between the gene signature risk score and overall survival was measured using Kaplan-Meier survival curves, univariate, and multivariable Cox regression analyses. ResultsPathway analysis findings indicate that ligand-gated ion channel pathways are the most significantly enriched with the genes in the aggregated signature. The aggregated signature described in this study is predictive of overall survival in oral cancer patients across demographic and treatment strata. ConclusionThis study reinforces previous findings supporting the role of ion channel gating, interleukin, calcitonin receptor, and keratinization pathways in tumor progression and treatment response in oral cancer. These results strengthen the argument that differential expression of genes within these pathways reduces tumor susceptibility to treatment. Conducting differential gene expression (DGE) with Monte Carlo cross validation, as this study describes, offers a potential solution to decreasing the variability in DGE results across future studies that are reliant upon highly heterogeneous datasets. This improves the ability of studies reliant upon similarly structured datasets to reach results that are reproducible.
Highlights
Head and neck cancers are cancers of the upper airway and/or digestive tract found in the oral cavity, laryngeal, pharyngeal, oropharyngeal, and hypo-pharyngeal tissues
Similar analyses were performed on gene signatures of genes randomly selected from the 20,530 genes in the Ligand-gated ion channel transport Defective pro-SFTPC causes pulmonary surfactant metabolism dysfunction 2 (SMDP2) and respiratory distress syndrome (RDS) Assembly of active LPL and LIPC lipase complexes Surfactant metabolism Formation of the cornified envelope Defective ABCA3 causes pulmonary surfactant metabolism dysfunction type 3 (SMDP3) Regulation of signaling by NODAL Calcitonin-like ligand receptors Plasma lipoprotein remodeling Class B/2 (Secretin family receptors) Keratinization POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation Interleukin-4 and 13 signaling
In addition to the identification of a signature that predicts overall survival in oral squamous cell cancers (OSCC) patients, this study validated the use of Monte Carlo cross validation in producing gene signatures that are more likely to be reproduced across multiple studies
Summary
Head and neck cancers are cancers of the upper airway and/or digestive tract found in the oral cavity, laryngeal, pharyngeal, oropharyngeal, and hypo-pharyngeal tissues. Head and neck cancer incidence has declined from 25 cases per 100,000 at risk in the 1990s to 15 cases per 100,000 at risk in the present day [3]. While the decrease in head and neck cancer incidence may be due to a drop in tobacco use [4,5], the mortality associated with these cancers has not changed significantly in the last twenty years [6]. Human Papilloma Virus (HPV) positive patients have been observed to have an improved survival and response to treatment when compared to HPV negative patients. These patients make up the minority of oral squamous cell cancers (OSCC) [7]. The decline in mortality could be attributed to decrease in smoking, increases in HPV positive cases, or other unknown mechanisms
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