In HPV-negative HNSCC, NRF2 overexpression is typically a consequence of mutations and copy number variations in its own gene and in the genes Keap1, Cul3 and RBX1 encoding for its regulatory complex, whereas NRF2 deregulation is caused by viral proteins in HPV-positive tumors [15,16,17]. The gene discussed is NFE2L2; the disease is head and neck squamous cell carcinoma.