Fig. 6: Summary of key events that occur during the evolution of cutaneous squamous cell carcinoma.

After continual exposures to UV radiation, fibroblasts modestly increase their mutation burdens, melanocytes sharply increase their mutation burdens, and keratinocytes have a mixed response. Most keratinocytes accumulate little mutational damage, but a subset with pathogenic mutations builds up mutations more rapidly than other skin cells. UV radiation induces expansion of independent clones of keratinocytes, often in close proximity and admixed, resulting in a complex clonal structure whereby adjacent lesions are not necessarily related. Driver mutations undergo selection in a stereotypical order, linked to histologic and genetic changes that occur during tumor evolution. An immune response builds during progression, but activity is blunted via engagement of immune checkpoints in squamous cell carcinoma.