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contain SMO oncogenic mutations compared with 25% of BCCs and 0% of SCCs [135] . BSCs also contained
all the other known BCC cancer drivers, MYCN, PP6C, GRIN2A, CSMD3, DCC, PREX2, APC, and
ARID1A at a frequency statistically similar to that of BCCs [135] .
SCC genetic drivers’ role in BSC
BSCs lack the classical SCC driver mutations, NOTCH1/2, HRAS/KRAS, and CDK2NA, at a frequency
expressed by SCCs. Instead, BSC contain SCC driver mutations at a significantly lower rate that is closer
to that seen in BCCs. The presence of classical BCC cancer drivers in BSCs and the lack of classical SCC
driver mutations suggests that BSCs have a mutational landscape similar to that of BCC, and that BSC
cancer drivers likely arise through the deregulation of SHH signaling [135] .
Genetics of cells modulating between BCC to SCC cells
It is believed that BSC originally derive from BCC due to their similar mutational landscape; they
subsequently acquire mutations that lead to squamatization [121] . Of the 20 cancer genes identified in BSC,
ARID1A is mutated in 45% of BSCs compared to 19% of BCC and 19% of SCC [125] . ARID1A normally
plays a role in the differentiation of several cancer types because it encodes a component of the chromatin
remodeling complex, SWI/SNF. SWI/SNF plays an important role in repairing damaged DNA, so ARID1A
impairment can cause defects in DNA repair. Disruption of ARID1A reduces the restrictive nature of
chromatin remodeling in terminally differentiated cells, imparting a plasticity that increases cell survival,
regeneration, and proliferation. Under selective pressure, such as a SMO inhibitor treatment, ARID1A
mutations allow keratinocytes to undergo squamatization, promoting de novo SCC development from
BCC [125] . Further research could be done to see if mutations within other components of chromatin
remodeling could confer plasticity in BSC.
Additionally, switching from the SHH pathway to the RAS/MAPK pathway is a form of crosstalk
between the pathways and another way that BCC can avoid selective pressures such as SMO inhibitors,
leading to squamatization. As discussed in the SCC section, an upregulated RAS/MAPK pathway can
lead to SCC. Pathway switching is believed to be driven by a loss of primary cilia, a microtubule-based
signaling organelle that is essential for high SHH pathway signaling, promoting RAS/MAPK signaling and
subsequent squamatization as seen in Figure 9. Furthermore, Gli1 is active in the nucleus and is typically
elevated in BCC. Stained BSC shows that basaloid keratinocytes demonstrate high Gli1 and low MAPK
staining which is similar to that of BCC. Squamatized keratinocytes in BSC demonstrate low Gli1 and high
MAPK staining which is similar to that of SCC. Interestingly, the transition zone shows a moderate MAPK
expression and high Gli1 expression, indicating that RAS-MAPK pathway activation drive squamatization
in BSC with subsequent loss of Gli1 expression as a secondary event. This discovery indicates the activation
of the RAS-MAPK pathway and subsequent reduction in SHH signaling as a potential modulator of tumor
plasticity in BSC [136] . Overall, tumor fate in BSC is believed to be dictated by a balance between SHH and
RAS/MAPK signaling [125] .
Calcium flux is a potential modulator of the balance between SHH and RAS/MAPK signaling in BSC.
The degree of extracellular calcium is a regulator of the SHH pathway. In rat gastric mucosal cells, SHH
is unable to activate extracellular signal-related kinases in calcium-free conditions. Conversely, cells in a
calcium-rich media show increased intracellular calcium levels, a marker for SHH pathway activation [137] .
Altogether, it is possible that calcium flux shifts the balance between SHH and RAS/MAPK signaling in
BSC, contributing to tumor plasticity [138] . More research is needed to establish a causal relationship between
calcium flux and the balance of SHH and RAS/MAPK. Future studies could be done to identify additional
modulators and to understand the interplay between existing modulators in conferring tumor plasticity.
Though it is known that BSC appear from BCC, it is unknown if these cutaneous lesions can also appear
from a SCC. However, due to the consistent state of flux that the body undergoes and crosstalk between