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Page 2 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60

discovered, genetic pathway mutations, this review stresses that these pathways are not fixed but rather exist in
dynamic, interrelated, interactive, complex, and adaptive flux states.

Keywords: Basal cell carcinoma, squamous cell carcinoma, verrucous carcinoma, basosquamous cell carcinoma,
melanoma, cutaneous T-cell lymphoma, genetic pathways, cancer hallmarks

INTRODUCTION
The molecular and genetic basis of the development of cutaneous malignancies involve multiple pathways
which continue to evolve over time. Tumor initiation, promotion, and progression leading to the
multiplication of abnormal cells are all effected by genetics, environmental factors, acute and chronic
exposures, diet, trauma, and many other factors. Angiogenesis and metastasis are likely influenced by host
dependent factors such as age and immunological status. Many skin malignancies environmental factors,
such as UV radiation that causes photocarcinogenesis, are coupled with genetic and epigenetic alterations
or extrinsic factors that contribute to local inflammation and dysregulation of normal pathways. Emerging
evidence supports the role of chronic inflammation in skin carcinogenesis mediated by factors including
nuclear factor-kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and hypoxia-
inducible factor-1 alpha (HIF-1α). In this article, we review validated models including the hedgehog
pathway for basal cell carcinomas, p53 (TP53) pathway for squamous cell carcinomas, and BRAF pathway
for cutaneous melanomas, among others. Additionally, we address emerging pathways that have not been
completely elucidated including those implicated in cutaneous T-cell lymphoma. We also review the
presumptive biology of less common skin cancers including basosquamous cell carcinoma and verrucous
carcinoma.

In this review we approach the role of genetic events in relationship to four interactive processes referred
to as “cancer hallmarks”. These signals must interact for cells which have undergone a carcinogenic event
to survive, proliferate, maintain a footing, and spread. The four hallmarks we review are: (1) malignant
cell growth; (2) prevention of apoptosis; (3) promoting use of supporting stroma and vascularization;
and (4) modulating and promoting an inadequate immune response. The genetic pathways of cutaneous
malignancies will be grouped as related to basal cell carcinoma, squamous cell carcinoma, verrucous
carcinoma, basosquamous cell carcinoma, melanoma, and cutaneous T-cell lymphoma. Nonetheless, this
review differs from most discussions concerning oncogenetics because we stress that these well-recognized,
as well as newly discovered, genetic pathway mutations are not fixed but rather exist in dynamic,
interrelated, interactive, complex, and adaptive flux states.

GENETICS OF BASAL CELL CARCINOMA
Nonmelanoma skin cancers (NMSC) include cancers affecting keratinocytes such as basal cell carcinoma
(BCC) and squamous cell carcinoma (SCC). This term also includes Merkel cell carcinoma (MCC), a rare
neuroendocrine tumor, and cutaneous T-cell lymphoma (CTCL). Four interactive processes referred to as
the four hallmarks must interact for cells which have undergone a carcinogenic event to survive, proliferate,
maintain a footing, and spread.

Malignant cell growth
Ultraviolet radiation
The most prevalent carcinogenic event promoting NMSC is ultraviolet radiation (UV) from sun exposure
[1]
and/or from other UV sources such as tanning beds . Skin damage from sun exposure modulates
tumorigenesis by damaging DNA, creating an inflammatory state, and activating oxidative stress responses,
[2]
receptor tyrosine kinases (RTK), and pro-apoptotic pathways . UV, a recognized carcinogen, penetrates