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the development of a tumor, either independently or in combination. There are multiple possible genetic
drivers capable of fostering the development of cSCC. Each of these drivers may influence the development
of a malignancy by impacting one of the four hallmark pathophysiological processes common to all
cancers. Depending on the provoking carcinogenesis, signaling mutations of the provoking carcinogenesis,
and crosstalk between the signaling of the hallmark processes, cSCC may have various aggressive potentials
and require various biogenic signaling-related therapies. This is a complex multi-factorial individualized
process overlapping signaling mutations that can be individually addressed therapeutically for cSCC.
It is important to note that all tumor cells are not created equally. In fact, the processes, mutations, and
pathways discussed above can occur at once within one tumor between multiple cells. GEP testing by Castle
Biosciences, Phoenix AZ, is being developed for SCC to assess gene upregulation and downregulation
within a given tumor for high and low risk patterns. This test will help determine metastasis risk among
high risk cSCC patients. Thus, the GEP test, when available, should help improve prognosis projections for
[96]
thus tumors labelled as poor prognosis cSCC .
GENETICS OF VERRUCOUS CARCINOMA
Verrucous carcinoma (VC), first described by Dr. Lauren Ackerman in 1948, is a rare variant of SCC,
usually in the oral mucosa. Risk factors for VC include HPV infection, smoking, chronic inflammation,
and repeated trauma. While the tumor generally has a good survival prognosis, it can be locally aggressive
and may recur after treatment. The mortality with VC is more often due to local invasion rather than
[97]
metastases . VC usually presents as a warty, exophytic, non-ulcerating lesion with a red/white surface,
making it difficult to clinically distinguish from other similar appearing dermatologic conditions. This
ambiguity leads to a lack of objective criteria for diagnosis, as well as challenges in establishing a definitive
method of treatment.

Malignant cell growth
While a definitive association has not yet been described, HPV infection may be a significant contributor
to VC. Plantar VC was shown to be associated with HPV type 16, while VC of the scalp was associated
with HPV type 33 [98,99] . E6 and E7 oncoprotein production by high-risk strains of HPV cause p53 and
retinoblastoma (RB) tumor suppressor inactivation, leading to cell cycle disruption and contributing to
the progression of VC [100] . The E6 protein forms a trimeric complex with p53, a tumor suppressor, and E6-
AP, a cellular ubiquitination enzyme [Figure 8]. This complex interferes with the functions of p53, leading
to uncontrolled cell growth. The RB protein normally binds to transcription factors of the E2F family,
which allows it to suppress replication enzyme genes like origin recognition complex 1, mini-chromosome
maintenance proteins, and cell division cycle 6 [101] . The E7 protein inhibits this interaction between E2F and
RB, allowing for uninhibited cell division and replication [102] .

Chronic inflammation is another hypothesized cause of cutaneous VC. VC has arisen in cases of decubitus
ulcers, hidradenitis suppurativa, epidermolysis bullosa, as well as chronic bladder inflammation by
schistosomiasis [103,104] . Chronic inflammation causes oxidative stress due to the release of cytokines,
prostaglandins, and TNF. This leads to genetic and epigenetic modifications including the inhibition
of DNA repair, modification of transcription, prevention of apoptosis, and stimulation of angiogenesis.
Inflammatory cells such as macrophages and T lymphocytes may express migration inhibitory factor (MIF),
81
which inhibits p53 transcriptional activity, leading to a loss of cell cycle regulation. The Cys residue of
MIF is thought to play a critical role in this association between MIF and p53, leading to the inhibition of
p53 mediated gene activation and apoptosis [105] . The loss of p53 contributes to a lack of response to DNA
damage, which increases the likelihood of carcinogenesis.

Repeated mechanical irritation also leads to DNA damage and resultant carcinogenesis [103] . Specifically, in
the case of epidermolysis bullosa, VC was thought to arise due to a mutation in the keratin 5 gene (KRT5).