Hence, EGFR amplification/overexpression, 18 differentially expressed FL transcripts, and enhanced immune rearrangements of IGKV4-1–IGKJ1, IGKV4-1–IGKJ2, IGKV4-1–IGKJ3, and IGKV4-1–IGKJ4 can be used as signature markers for characterizing keratinized OSCC with MD/PD/WD with lymphadenopathy and may play an important role in controlling the premalignant phenotype of keratinized OSCC and progression of the disease. This evidence concerns the gene IGKV4-1 and Menkes disease.