In conclusion, we highlight the potentially relevant impact of the findings concerning (i) the mutagenic process driven by APOBEC family members in response to chronic tissue damage; (ii) the role of NOTCH1 mutations/NOTCH pathway in SCC development; (iii) the action of inflammatory mediators, in particular, IL-6, in tumor progression and spreading; (iv) the impact of wound bacterial colonization and immunity in carcinogenesis; (v) the use of circulating molecules and extracellular-vesicles as novel, minimally-invasive diagnostic and prognostic factors of the disease. The gene discussed is NOTCH1; the disease is neoplasm.