Our findings for AT-84 and SCC VII of C3H background demonstrate their high resemblance to HNC patient tumors, in capturing diverse mutational signatures relevant to HNC tumorigenesis, and key gene copy increases including Pik3ca, Rptor, and Ctcf. Importantly, mutational profile analyses of all five models show genetic defects on 10 cancer hallmarks and 14 HNC-relevant signaling pathways and machineries (including epigenetic regulatory, metabolic regulatory, and immune evasion machineries) to extents similar to HNC patients (TCGA). The gene discussed is CTCF; the disease is cancer.