Signaling Networks in Methylated HPV Genomes

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Objective: HPV-positive (+) and HPV-negative (–) HNSCC are biologically distinct with a prognostic advantage for HPV+ patients compared to HPV– cases. The goal of this study was to identify differentially methylated genes in HPV+ vs HPV– primary HNSCC genomes with clues to signaling networks that impact key biological functions. Method: DNA from 4 HPV(+) and 4 HPV(–) freshly frozen primary HNSCC were subject to comprehensive genome-wide methylation profiling using the HumanMethylation27 Bead Array, which measures methylation as a β value ranging from 0 to 1. Genomatix Pathway System software was applied to build a network from differentially methylated genes. Results: Two-fold methylation differences were observed between HPV+ and HPV– cases for 1168 genes. Pathway analysis applied to investigate the biological role of the 1168 differentially methylated genes revealed 8 signals transduction pathways forming a network of 66 genes, of which 62% are hypermethylated (41 of the 66). Of the 8 signal transduction pathways, the Beta catenin degradation, E-cadherin, ErbB receptor, and Integrin signaling networks have immediate association with HNSCC. The other 4 pathways are c-kit, ion channels, ppara elements, and RXR and RAR heterodimerization signaling events. Conclusion: Signaling events in the cell play a critical role in the execution of key biological functions. Our results demonstrate that in signal transduction pathways, HPV genomes harbor a larger proportion of hypermethylated genes than HPV-negative tumors with potential for these genes as differential targets in HPV related HNSCC.