The leading-edge analysis revealed that 18 core genes were significantly enriched in HPV-related HNSCC patients, including CDKN2A, DDB2, DUT, ERAP1, GLS2, MDM2, MLH1, NOTCH1, PCNA, POLH, PPM1D, PTTG1, SYK that were up-regulated in HPV+ HNSCC patients, however, CAV1, CD44, FLT1, ME1, and RTN4 were up-regulated in HPV- HNSCC patients (Figure 4). This evidence concerns the gene RTN4 and head and neck squamous cell carcinoma.