Characterization of ferroptosis driver gene signature in head and neck squamous cell carcinoma (HNSC)

Background: Head and neck squamous cell carcinoma (HNSC), a prevalent malignant tumor with a low survival rate, is often accompanied by ferroptosis, which is a recently-described type ofprogrammed cell death. Investigating the significance of ferroptosis driver genes in HNSC, this study aimed to assess their diagnostic and prognostic values, as well as their impact on treatment and tumor immune function. The results of this investigation provide novel insight into using ferroptosis-related genes as molecular biomarkers as well as precise chemotherapeutic targets for the therapy of HNSC. Methodology: A detailed in silico and in vitro experiment-based methodology was adopted to achieve the goals. Results: A total of 233 ferroptosis driver genes were downloaded from the FerrDB database. After comprehensively analyzing these 233 ferroptosis driver genes by various TCGA databases, RNA sequencing (RNA-seq), and Reverse Transcription Quantitative Real-Time Polymerase Chain Reaction (RT-qPCR) techniques, TP53 (tumor protein 53), PTEN (Phosphatase and TENsin homolog deleted on chromosome 10), KRAS (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), and HRAS (Harvey Rat sarcoma virus) were identified as differentially expressed hub genes. Interestingly, these hub genes were found to have significant (P < 0.05) variations in their mRNA and protein expressions and effects on overall survival of the HNSC patients. Moreover, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes (TP53, PTEN, KRAS, and HRAS). In addition to this, hub genes were involved in diverse oncogenic pathways. Conclusion: Since HNSC pathogenesis is a complex process, using ferroptosis driver hub genes (TP53, PTEN, KRAS, and HRAS) as a diagnostic and prognostic tool, and therapeutically targeting those genes through appropriate drugs could bring a milestone change in the drug discovery and management and survival in HNSC.