Table 1.

Mutated genes involved in the development of AKs and SCCs.

Gene	Role
TP53	The most involved mutated gene in all types of cancers, but also in SCCs [18]. TP53 gene encodes p53 protein which plays a vital role in cell cycle. Even though mutations in TP53 gene appears early in the evolution of SCCs, they cannot represent the sole mutation needed for cancerous progression [19].
NOTCH	Loss of function of NOTCH gene represents a premature sign of the conversion of healthy keratinocytes to their precancerous version [12,20]. Mutation of NOTCH genes has been found in both SCCs and dermoscopy-free dysplastic lesions that has been chronically exposed to sun, thus suggesting that NOTCH mutation can be considered a trademark for UV-damaged keratinocytes [21,22].
RAS	RAS mutation is characteristic for cSCCs developed in patients treated with Vemurafenib, a B-Raf inhibitor [23]. It is a rare spontaneous mutation in cSCCs [20,24].
CDKN2A	It encodes p16INK4a and p14ARF, which have the role of tumor-suppressor proteins [25]. p16INK4a inhibits cyclin D-dependent kinases in a direct manner, leading to the activation of retinoblastoma protein (RB) [26]. p14ARF isolates Mdm2 inside the nucleolus, preventing its interaction with p53 [27,28]. Mutation of CDKN2A plays an important role in both the appearance of AKs and the evolution of AKs to SCC [29]
PIK3CA	PIK3CA mutations were found in almost half of the cohort in a study, including AKs and SCCs, while in another cohort involving head and neck SCCs, ⅓ was found [24]. Tirbanibulin 1% ointment is used in the topical treatment of AKs with good efficacy, being based on a Src kinase inhibitor that acts on inhibiting PI3K (phosphatidylinositol 3-kinase) [30].
KNSTRN	It is considered to be part of the “UVB signature” [17]. It encodes a kinetochore protein that leads to the disruption of chromatin cohesion and, thus, aneuploidy and tumorigenesis [24].
FAT1	It encodes a protocadherin that can lead either to aberrant Wnt/β-catenin signaling or to increased CDK6 expression [31].
CARD11	CARD11 gene encodes a protein that scaffolds the role of nuclear factor kappa B (NF-kB) [32]. CARD11 mutations are found in UV-exposed skin and in the skin surrounding cSCC, and they have a role in the progression from normal to cancerous keratinocytes [33].
SRCASM	It encodes a tumor suppressor molecule with a VHS site, a GAT site, and multiple tyrosine phosphorylation domains [34]. Src-family tyrosine kinase (SFK) phosphorylation of the above molecule leads to limitation of keratinocyte proliferation and engagement in keratinocyte differentiation [34]. Both SCCISs and SCCs are associated with reduced SRCASM levels and a raised activity of SFKs [35,36].
TP63	TP63 gene encodes p63 protein, which is commonly found to be overexpressed in cSCCs [37].
EGFR	EGFR is found to be dysregulated in the development of cSCCs [38]. EGFR is involved in keratinocyte proliferation and differentiation and also influences the rate of survival of these cells [39].