Genetics of Skin Cancer Diagnostics and Treatment
Received: 20-Nov-2018 / Accepted Date: 22-Nov-2018 / Published Date: 30-Nov-2018
Diseases evolve side by side with human evolution and play significant role in health. Along with the societal and technological development, mankind also faces great challenges in health sector. One of these challenges is the changes in disease manifestation, its cure and obviously its effect on living organisms especially humans, which has worsen as time progresses. Some of the diseases are easily treatable now while other still poses complications. Skin cancer is one of the most common and widespread cancers despite technological and medicinal advancements and demands persistent attention. It is categorized into different types according to its location of origination and usually these cancers do not spread to other body parts. Various environmental and genetic factors contribute in its occurrence, development and metastasis. People with blonde skin tone are at supreme risk to be affected by melanoma. Considering the importance of this disease, the current review concentrates on the various types of skin tumors, its manifestations, the causes behind disease development and treatment. Genetical mutations in somatic cells or at fetus level play major role in its establishment. Furthermore, environmental factors also affect the normal cellular pathways by bringing about the alterations at gene level. Prudent analysis of the genetics may lead to better understanding of the key genes involved in its establishment and thus, the pertinent knowledge can be utilized in designing painless and accurate diagnostic approaches and advanced targeted therapies.
Keywords: Skin cancer; Diagnosis; Treatment; Genetic factors; Metastasis
Skin cancer is basically damaged skin cells which keep on growing abnormally. Upon every expose to UV radiation, hazardous material and corrosive chemicals, there is a fair chance of structural and functional alterations in skin cells, which in turn leads to skin cancer. With the passage of time, these damages become more serious and worse. Repetitive exposures further increase the cancer risk. At any age, many sun protection products help in prevention of skin cancer and melanoma . Skin cancer is named after the cell type in which the cancer expands. There are three major types of skin cancer:
1. Basal cell carcinoma
2. Squamous cell carcinoma
Basal and squamous cell carcinoma are non-melanoma cancers, but melanoma is most serious type of skin cancer. Melanoma includes Merkel cell tumor and dermato-fibrosarcomaprotruberans. Like all cancers, early diagnosis of skin cancer results in better treatment. Area of the skin which is cancer affected looks different from the other body parts. Even a small blemish should be taken seriously and it is significant to be checked out. Skin cancer usually looks as new blemish. Sometimes it appears as presented spot which get in different color, shape or size . In white population, Melanoma skin cancer (MSC) and Non melanoma skin cancer (NMSC) are the main types of skin cancer. Prevalence of skin cancer has attained epidemic magnitude. Recently conducted studies on population has showed that the basal cell carcinoma’s incidence rate in males is over 2% while that for squamous cell carcinoma is 1%, and rate of new cases of melanoma is about 50 per 100 000 of population .
Basal cell carcinoma is widely spread cancer type but not dangerous one. It mostly looks like a dry scale or lump of pale or red color having slow growth rate. It is usually seen on neck, head and upper torso . With gradual growth, it leads to ulcer which doesn’t heal completely. Even upon healing, there is a fair chance for a second outbreak. Squamous cell carcinoma is also not a major health threat when compared to other forms of cancer. In case of negligence, it can spread to other body parts. The growth take months when expose to sun. It appears as scaly blemish of red color. This blemish can bleed or ulcerate easily. Both these Non-Melanoma Skin Cancers (NMSC) are not dangerous as Melanoma Skin Cancer (MSC) [3-5].
It is the most dangerous type of skin cancer with a rapid growth frequency. If neglected, it can lead to serious life-threatening form within six weeks. It appears as flat blotch on skin usually having different colors – brown, blue, black, grey or red, not usually expose to sun .
It is an exceedingly dangerous type of melanoma that appears differently from ordinary melanomas – it is extreme from the beginning. It appears as red, pink, black or brown blemishes. It grows very quickly and can be life-threatening in case of negligence or if left unattended. Some harmless ciphers of sun damaged skin are freckles, moles, marks, stains, blemishes, spots, and blotches etc. [5,6].
Basics Of Skin Cancers
Among skin cancer, majority of cases are either basal or squamous cells carcinoma. These types do not spread to other body part. If untreated, results in disfiguring locally. Melanomas are termed malignant if they spread to other body parts. It is of small number and extremely aggressive cancer. If untreated, results in life-threat . Skin cancers initiate as the precancerous lesions. Initially these lesions are not cancerous but can change into cancer with the passage of time. It is medically referred as dysplasia. Actinic keratosis grows into squamous cell carcinoma . Nevus is a mole which abnormally develops into dysplastic nevi. Dysplastic-nevi are not actual cancer, but can change into the real cancer. Usually people have many moles on the body, around 10 to 30, which may appear as smooth, raised, round in form, tan or skin-colored, and not more than quarter-inch in size. Sometimes, people have 100 or even more dysplastic-nevi, which are asymmetrical in shape, with serrated borders and “pebbly”, one should go to their healthcare center, if they observe any change in normal moles on the skin .
Sunlight is major risk factor for skin cancer. Ultraviolet Radiation (UVR) is biologically vigorous constituent of sunlight. The extremely carcinogenic range of UVR is 290-320 nm Ultraviolet B (UVB) while 320-400 nm Ultraviolet A (UVA) is lesser carcinogenic [9,10]. Other risk factors for skin cancer comprises of diet, stress, hormone therapy, hair dyes, smoking, fluorescent lighting. Use of tanning parlors and sun beds are also the cause of melanoma . Other causes include immuno-suppression, or mutilation of immune system . Revelation to X-rays or other high level radiations can develop skin cancer, even exposure to certain chemicals, such as arsenic and hydrocarbons in oils, tar, or soot result in carcinoma. People on supreme risk of melanoma are those with blonde skin, which freckles, sunburn easily. Those with flaxen hair, blue or green eyes, abnormal orabundant moles, previous history of treated cancer and history of skin cancer in closest relative are at greater risk of skin cancer development . Genetic disorders that cause depletion of skin pigment, for example albinism and xerodermapigmentosum can result in skin cancer progression in those people . Age can be another factor of basal and squamous cell carcinomas. But age specifically has nothing to do with melanomas and it can develop in young people about 25 to 29 years old. .
Genetics And Skin Cancer
Glutathione S-transferasegenes (GST)
Glutathione S-transferase belongs to a super gene family and is major phase II detoxification enzymes . Its different classes are mentioned in Table 1. As detoxification enzymes, one of their fundamental functions in providing defense against carcinogen associated DNA damage is to detoxify the exogenous substances like chemotherapeutic agents and Reactive Oxygen Species (ROS). Alteration in GST-P1 genotype is reported to be associated with skin cancer . Its Ile105Val polymorphism causes the reduction in enzyme activity and is reported to be associated with malignant melanomas in Asian and Caucasian populations . Its allele GST-P1*A is reportedly associated with higher risk of NMSC and GST-M1 null with higher risk of BCC in transplanted patients in Italian population . Contradictory to that, GST-M1 positive genotype is reported associated with SCC in Japanese population  and its allele GST-M1*AB and GST-M3*AA are found associated with SCC in Australian renal transplant recipients .
|Class or super family||Gene||Allele||References|
|Alpha||GSTA2||GSTA2*A||YuanJ-M et al. ,
Lira et al. 
|Mu||GSTM1||GSTM1*A||Lira et al. ,
Chiyomaru et al. 
|Pi||GSTP1||GSTP1*A||Sheehan et al. |
Table 1: Different polymorphic forms of human glutathione-S-transferases.
Keratin 17 (K17) is tough, fibrous protein that forms the structural framework of certain cells including skin. It is involved in the regulation of the cell growth signaling and cytokine expression . Many studies points at the correlation of the K17 with the development of the skin tumors [23,24]. Deletion of K17 gene in mouse model caused the reduction in the keratinocyte proliferation, inflammation and immune response polarization from Th1 and Th2. This ultimately lead to the delay in tumor onset . K17 binds with hnRNA which is RNA binding protein and take it to cytoplasm where it regulates the expression of many pro-inflammatory mRNAs including CXCR3  whose elevated expressions are associated with tumor cell growth and invasion . Further, caspase-7 lower levels in skin tumors also promotes the SSL-induced skin carcinogenesis by blocking caspase-7- mediated cleavage of keratin-17 .
Lysyl oxidase-like 2
Lysyl oxidase-like 2 (LOXL2) is a member of lysyl oxidase (LOX) family which consists of five closely related proteins (LOX and LOXL1– LOXL4). It is involved in both intracellular and extracellular functions of the cell and has effect on gene transcription, cell motility, cellular adhesion, angiogenesis and differentiation [27,28]. Its increased expression is reported in malignant tumor . Loxl2 down regulates the NOTCH1 signaling pathway  which is involved in promoting differentiation and tumor suppression .
Krüppel-like factor 4
Krüppel-like factor 4 (KLF4) is a zinc finger protein which is formerly recognized as gut-enriched Krüppel-like factor (GKLF). It contains a transcriptional domain and is expressed in terminally differentiated epithelial cells of the thymus, gut, oral cavity and skin [31,32]. It is involved in cell differentiation and causes G1/S arrest if damage to DNA occurs . Its elevated mRNA and protein levels in SCC are reportedly associated with skin SCC progression and metastasis . These finding are quite contradictory to the studies of Yoon et al.  and requires further experimental proves.
Vitamin D and skin cancer
Vitamin D is a pro-hormone and secosteroid and is produced in the skin, which is the only identified organ system able to produce all the components having role in the vitamin D signaling pathway after exposure to ultraviolet light B (UVB; 290–320 nm) [35,36]. Different types of vitamin D and their functions are mentioned in Table 2. An association between vitamin D synthesis and UV exposure has been reported in numerous epidemiological studies. UVB is the major etiologic factor in inducing NMSC and it also triggers the vitamin D production cutaneously [37,38]. The production of vitamin D in skin is reported to directly lower the incidences of cancer. In a casecontrol study of elderly men, a lower frequency of NMSC was reported in subjects having higher levels of the pre-vitamin D metabolites in serum as compared to the subjects having lower concentrations . Moreover, enhanced pre-vitamin D concentrations in plasma have also been reportedly associated with longer survival along with decreased metastasis . For vitamin D to function properly, its receptor named as Vitamin D receptor must be present. In case of malignant melanoma, its expression is hindered and recuperation of its expression often results in tumor cells death and reduction in metastasis [40-42]. A VDR positive mouse model xenografted with human-derived malignant melanomas has been reported to suppress tumor growth via vitamin D receptors  while 1,25-D3 induced apoptosis in the human malignant melanoma cell line . Vitamin D sub-junction in melanoma cells up-regulates CYP24A1 mRNA, leading to the deactivation of MAPK signaling pathways which may partly control the anti-proliferative effects of vitamin D .
|7-dehydrocholestrol||Previtamin-D3||Cholesterol precursor||Biologically inactive||Webb and Grant etal. [35,36]|
|Vitamin D2||Ergocholecalciferol||Plants and fungi||Biologically inactive|
|Vitamin D3||Cholecalciferol; activated 7-dehydrocholesterol||Skin (following sun exposure); fish and meat||Biologically inactive|
|25-hydroxyvitamin D3||25-D3, calcidiol, calcifediol||Production induced by hydroxylation of vitamin D3 in the liver||Inactivation of vitamin D receptor”|
|1,25dihydroxyvitamin D3||1,25-D3, 1,25dihydroxycholecalciferol, calcitriol||25hydroxyvitamin D is further hydroxylated in the kidneys by 1alphahydroxylase||Primary biologically active form of vitamin D; activates the vitamin D receptor|
Table 2: Vitamin D types and its functions.
Few other genes are also found inactivated during skin tumor development. Restoration of their expression results in the tumor suppression and induced apoptosis. p53 is one such gene which is actually a stress induced transcription factor and in around 50% of all SCCs, various inactivating mutations causes its functional inactivation . FOS and c-Jun are the members of the transcription factor complex AP-1whose elevated levels in tumor cells are reported to assist melanoma development by throttling the p53tumor-suppressive function via direct transcriptional repression [44,45]. Other than that mapping of several susceptibility loci for cutaneous malignant melanoma (CMM) have been done. CMM1 susceptibility loci are reported to be located on chromosome 1p36, mutations in the CDKN2A gene on chromosome 9p21 is reported associated with CMM2 and mutations in the CDK4 gene on chromosome12q14 are reported associated with CMM3. CMM4 has been linked to chromosome 1p22 . But these susceptibility loci mapping is not enough, further study is needed to find more loci linked to this cancer. Several genes like STK11, BRAF, DCC, TRRAP, PTEN, BAP1, ZNF831 and GRIN2A have been reported to contain sporadic somatic mutations which may be the cause of malignant melanoma . These genes require further study in depth to understand the molecular effects of these mutations on gene product and its further effect on cell’s normal physiology that leads to tumor.
There are different symptoms depending on skin cancer types. BCC appear as raised, smooth, lustrous smack or un-healable sore on head, neck, or shoulders when exposed to sun. Sometimes, even blood vessels get visible and frequent ulceration in tumor. On sun-exposure, SCC appears as well-defined, scaling, thickened bash. If neglected, ulceration can develop into large mass. Melanomas are of different size, shape, abnormal moles, brown to black pigmented laceration. It also appear as newly develop mole, itching or ulceration in adulthood .
Physical examination and biopsies are used to diagnose skin cancer. In medical biopsy, part or whole blemish is removed and then sent to laboratory for procedure. Since it is quick and simple diagnostic method, results can be obtained within a week. A mole or lesion can develop into skin cancer hence getting it checked by a dermatologist is useful option for early diagnosis. Dermatologist uses a simple procedure; first Mela Find is used to scrutinize the lesion, then computer simulated image evaluation is used to specify if lesions are cancerous . After that, sample is taken for biopsy to examine underneath microscope. If biopsy reveals malignant melanoma, further blood tests and chest X-ray is proceeded .
Age and general health are two important scenarios to be considered for best treatment. Treatment can also depend upon type, size, shape and spread of the cancer. Normally straightforward methods such as surgery, freezing and scraping are used for BCC and SCC treatment [51,52]. Moreover, topical creams (Imiquimod therapy) , topical photodynamic therapy (PDT)  and cytostatic agent 5-fluorouracil  have been approved for non-melanomacancer treatment. For malignant melanoma complex methods of treatment are required such as immunotherapy, chemotherapy and radiotherapy mediated treatment . Different techniques i.e., simple excision, electrodesiccation and curettage, and cryosurgery are used to remove the small lesions of skin cancer . Mohs micrographic surgery is used to remove the larger tumors, recurrent tumors and lesions in cosmetically sensitive areas and high-risk locations. In this technique, the tissue is removed very carefully, layer by layer, till the appearance of cancer-free tissue [57,58]. Mostly skin cancer gets cured after surgical treatment. Of the skin cancers that do reappear, most of them do so within the period of three years. In case of advanced malignant melanoma, one should consult their oncologist every few months. Regional lymph node checks, periodic chest X-rays and body scans and total body skin exams should be carried out during these visits . Evidences from epidemiological studies indicate that avoiding smoking and intense sun exposure, controlling the infections, decrease of alcohol consumption, increased intake of fruits and vegetables, and increase in physical activity will effectively reduce the rates of cancer [60-62]. IFN-α helps in boosting the immune system and help with removal of the leftover melanoma cells post-surgery. Its antitumor activity in advanced cancer disorders is an added advantage . Vismodegib, a hedgehog signaling pathway inhibitors has proved remarkably efficient and proved to be efficient treatment option for patient with skin cancers. If cases where a tumor is risky to operate or the radiation therapy is not advisable, vismodegib treatment has resulted in complete remission in 21% of locally advanced BCC . The utilization of nanotechnologies for plethora of biomedical applications has sparked new trend worldwide . Nanomaterials have been explored extensively to improve the potency of anticancer treatment using targeted drug delivery . A variety of nanomaterials have been explored for their potential role in order to treat skin cancer. Some key examples include utilization of dendrimers, liposomes, polymersomes, protein based nanoparticles, inorganic nanoparticles and carbon-based nanoparticles as next generation delivery systems for targeted anticancer treatment strategies .
With every passing day, skin cancer is becoming the primary reason of several mundane deaths. One of the major causes of its occurrence is exposure to UVR which in most cases, one cannot avoid. So, instead of suggesting ideas to minimize sun exposure like the use of sun block creams which do more harm than good, scientist must find natural sources which neutralize UVR effect. Vitamin D in this regard has experimentally proven to be very effective in minimizing the chances of skin tumor development and also in suppressing tumor growth. The treatment and diagnostic strategies also need improvement as early detection of tumor have its benefits in providing timely proper treatment. Further, chemo- and radio-therapy are traditional ways of treating cancers which are not specific and patients have to go through many physical changes that are very embarrassing and discouraging for them. This not only lowers the patient self-esteem but also effects recovery rate. Modern treatment methods include topical creams and immunotherapy which are less painful and are more specific to tumors. Still further improvements are required in the treatment of skin cancer.
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Citation: Muzamil S, Ullah MA, Khan MA, Jan SU, Hina (2018) Genetics of Skin Cancer Diagnostics and Treatment. J Oncol Res Treat 3: 127.
Copyright: © 2018 Muzamil S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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