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Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60 Page 31 of 40

Initiators and promoters
There are different provoking aspects that cause cutaneous malignancies. Promoters are products or a low-
level exposure a carcinogen that can begin the process of tumorigenesis but not quite reach the threshold
to create full DNA mutations. Exposome is the combined exposure to all factors that cause internal
chemical environment change [220] . Promoters, however, can change gene expression that leads uncontrolled
growth. Initiators are factors that begin the process of DNA mutation and alteration in structure. It is
not the exposure to one carcinogenic chemical or product that immediately causes DNA mutation and
tumorigenesis, but it is the initial exposure that primes the tumor cells to change the function of certain
genes. Eventually, the exposome can promote tumors to form [220] . It is also not just the exposure to one
carcinogen in low doses but the repeated exposure to multiple carcinogens. In the case of cutaneous
malignancies, solar UV is seen as a carcinogen that can either work as a promoter, an initiator, or both a
promoter and initiator depending on the amount of exposure and protective measures. Moreover, studies
have found that children exposed to the high-level UV from Western Australian sun have been found
to have varying risk of cutaneous malignancies. Patients that arrive to Western Australia prior to age 10
have a 50% increased risk of dysplastic nevi or melanoma compared to those who arrive after the age of
10 regardless of their time spent sunbathing. This factor is due to the solar UV in Western Australia being
higher of many other countries from where patients immigrate. Solar UV acting as an initiator and/or
promoter for cutaneous malignancies explain the importance of protecting the skin from solar UV at all
costs regardless of Fitzpatrick skin type. There is a need for further research to find other carcinogens that
can act as initiators and/or promoters that to help patients prevent from these cancer-causing factors [221] .

Effects of mi-RNAs
Genetic testing and gene therapy might be the future for patients with cutaneous malignancies. As
previously stated, Castle Biosciences has already created testing to further determine staging and
implication for sentinel node testing for melanoma and metastatic risk for SCC. However, the genetic
testing does not stop there. miRNA plays an important role in signaling pathways determining the
activation and suppression of specific genes for transcription factors. As mentioned in the previous
sections, miRNAs can cause hypomethylation of genes leading to increased transcription, translation, and
uncontrolled proliferation. Many of these genes are upregulated and downregulated having different effects
on the genes; these effects can also lead to the appearance and progression of these cutaneous cancers.
Moreover, SCC, VC, and CTCL have all been found to be incited by miRNAs. There are hundreds to
thousands of miRNAs that can transform the function of genetic pathways and transcription factors from
a normal functioning pathway to a malignant pathway. With this information, miRNAs can be a subject of
research to help further test patients and possibly place them in complete remission as well as prophylaxis
to prevent the next cutaneous malignancy from appearing.

Further genetic testing
In addition to genetic testing and therapy, there are many more topics within genetics that have room for
further research. Many of the genetic tests performed are through somatic genetic testing and germline
genetic testing. The germline testing is done through either saliva or lymphocytes. However, studies
have found that within the saliva of patients with systematic lupus erythematosus, their salivary DNA
[222]
has adapted the DNA of their food products . “You are what you eat”. This information can be helpful;
however, with determining the somatic genetic susceptibility of cutaneous malignancies, there must be a
way to determine the difference between the genetic makeup of the food consumed and that of the patient’s
unmutated, unincorporated somatic cell DNA and RNA. This can be a problem with lymphocytes as well.
T- and B-lymphocytes have specific genetic makeup that turns them into the subtype of mature T- and
B-lymphocytes. Yet, when T- and B-lymphocytes are presented with a specific antigen or allergen, their
genetic makeup can also transform to program the lymphocyte for either attack of the antigen or produce
antibodies towards the antigen, respectively. Additionally, lymphocytes can change their genetic code