**3. Risk factors**

There are multiple risk factors that contribute to escalating incidence of melanomas in humans (Table 1). Ultraviolet (UV) radiation especially UVA (315-400 nm) and UVB (280-315 nm) from sunlight is an important contributing factor for melanoma progression. A study by Glanz et al [5,12] revealed that 90% of all melanomas are attributed to exposure to ultraviolet radiation.

The damaging effects of UV radiation (UVR) is on account of direct cellular damage and alterations in immunologic functions. UVR causes DNA damage (by formation of pyrimidine dimers), gene mutations, oxidative stress, immunosuppressive and inflammatory responses. All these effects play an important role in photoaging of the skin and predispose to skin cancer [13]. UVR creates mutations in p53, a key tumor suppressor gene that plays an important role in DNA repair and apoptosis. Thus if p53 is mutated, the cells lose the DNA repair process leading to the deregulation of apoptosis, expression of mutated keratinocytes and initiation of skin cancer [13,14]. Darker skinned individuals have lower incidence of cutaneous melanoma primarily as a result of increased epidermal melanin. Studies indicate that epidermal melanin in African-American individuals filters twice as much UVB radiation than in Caucasians. This is on account of the larger, more melanized melanosomes located in the epidermis of dark skin individuals that absorb and scatter more light energy than the smaller, less melanized melanosomes of white skin. The incidence rate of skin cancer (both melanoma and nonmelanoma) has increased significantly in the last decade [15]; particularly among young women. For most individuals, exposure to UVR from the sun is the main source of skin cancer. Nonetheless, some individuals are exposed to high UV doses through artificial sources – sunbeds and sunlamps used for tanning purposes. Indoor tanning is widespread in most developed countries in Northern Europe, Australia and the United States [16]. Intense early sunburns and blistering sunburns are closely associated with melanoma development [17,18, 19]. Statistics indicate that one severe childhood sunburn is associated with a two-fold increase in melanoma risk [20]. Chronic UV exposure results in increased skin aging, wrinkles, uneven skin pigmentation, loss of elasticity and a distribution in the skin barrier function [21]. Chronic UVR exposure is an important risk factor in the development of actinic keratosis (precursor of SCCs).

#### **Ultraviolet (UV radiation)** UVA UVB

#### **Genetic syndromes**

Xeroderma pigmentosum Oculocutaneous albinism Basal cell nevus syndrome

#### **Ionizing radiation**

X-rays

#### **Other risk factors**

Artificial UV radiation (tanning) Smoking Color of skin (having fair skin, especially with blue or hazel eyes) History of precursor lesions Chronically injured or non-healing wounds Working outdoors Increasing age

**Table 1.** Risk factors for skin cancer [1-8]

among individuals with albinism and Xeroderma Pigmentosum. These disorders can be

**b.** Squamous Cell Carcinoma (SCC): This cancer begins in the squamous cells that form the surface of the skin, lining of hollow organs of the respiratory and digestive tracts. The earliest form of SCC is called as actinic keratosis (AK) [2] that appear as rough, red bumps on the scalp, face, ears and back of the hands. The rate at which the bumps (keratosis) invade deeper in the skin to become fully developed squamous cell carcinoma is estimated to be 10-20% over a 10 year period. Actinic keratinosis that becomes thicker and more tender could increase the possibility of getting transformed to an invasive squamous cell carcinoma phenotype. The most important risk factor is sun exposure. Lesions appear after years of sun damage in the forehead, cheeks as well as the backs of hands. Other minor factors like exposure to hydrocarbons, arsenic, heat or X-rays could predispose to

SCCs. Unlike BCC, SCCs can metastasize to other parts but are easy to treat.

the progression of melanoma, the cancer gains metastatic potential.

**3. Risk factors**

44 Highlights in Skin Cancer

to ultraviolet radiation.

**c.** Melanoma: This is the cancer of the melanocytes, the "skin-color producing cells" of the body. An estimated 132,000 new cases of melanoma occur worldwide every year [5,6,7] with approximately 65,161 deaths according to estimates from the World Health Organ‐ ization (WHO). The high mortality rate of melanoma is remarkably high considering the fact that melanoma is nearly always curable in its early stages; the high mortality rate can be attributed to late diagnosis in which the cancer spreads to other parts of the body [5]. Melanoma incidence has increased more rapidly than that of any other cancer, yet our ability to treat disseminated disease has been lagging [8,9,10]. The predicted 1 year survival for Stage IV melanoma ranges between 41% to 59% [11]. At a very early point in

There are multiple risk factors that contribute to escalating incidence of melanomas in humans (Table 1). Ultraviolet (UV) radiation especially UVA (315-400 nm) and UVB (280-315 nm) from sunlight is an important contributing factor for melanoma progression. A study by Glanz et al [5,12] revealed that 90% of all melanomas are attributed to exposure

The damaging effects of UV radiation (UVR) is on account of direct cellular damage and alterations in immunologic functions. UVR causes DNA damage (by formation of pyrimidine dimers), gene mutations, oxidative stress, immunosuppressive and inflammatory responses. All these effects play an important role in photoaging of the skin and predispose to skin cancer [13]. UVR creates mutations in p53, a key tumor suppressor gene that plays an important role in DNA repair and apoptosis. Thus if p53 is mutated, the cells lose the DNA repair process leading to the deregulation of apoptosis, expression of mutated keratinocytes and initiation of skin cancer [13,14]. Darker skinned individuals have lower incidence of cutaneous melanoma primarily as a result of increased epidermal melanin. Studies indicate that epidermal melanin in African-American individuals filters twice as much UVB radiation than in Caucasians. This

linked to either instability of the skin or diminished pigmentation.


**Gene Protein Function Commentary References**

*CDH2* N-cadherin Cell-cell adhesion Melanoma invasiveness [144,145]

*SPP1* Osteopontin Inductor of MMP Risk of metastasis [144,147] *SPARC* Osteonectin Angiogenesis Tumor progression [144] *WNT5A* Wnt5a Cell signaling Melanoma invasiveness [125,148]

*EIF2gamma* EIF2γ DNA translation Tumor progression [149]

*CDH3* P-cadherin Cell-cell adhesion Tumor progression [145,151] *CDH10* Cadherin-10 Cell-cell adhesion High risk of metastasis [144]

Acquisition of somatic mutations in key regulatory genes is the driving force behind the initiation and progression of melanoma development. For the past few decades numerous research teams around the world have researched on melanoma genetics leading to an

Approximately 8-12% of all melanomas are familial – occurring in individuals with a history of familial melanoma [24]. Two genes have been found to be associated with high pene‐ trance susceptibility – CDKN2A and CDK4. Using linkage analysis of families with high melanoma incidences, the first melanoma incidence susceptibility gene, CDK2N2A was identified at chromosome 9p21 [25,26]. The gene CDKN2A encodes two unrelated pro‐ teins – p16Ink4A and p14Arf. These proteins are tumor suppressors involved in cell cycle regulation. Numerous studies indicate that p16Ink4A inhibits G1 cyclin dependent kinase (cdk4/cdkb) mediated phosphorylation of retinoblastoma protein (pRB) resulting in cell

Cofactor DNA polymerase

Desmosomal component

**Table 3.** Genetic expression signatures associated with the progression of melanomas [24]


kinase subunit 2 Cell cycle control Poor prognosis [147]

E-cadherin Cell-cell adhesion Tumor progression [144,145,147]

damage response Melanocytic infiltration [135,136,137]

An Overview of Important Genetic Aspects in Melanoma

http://dx.doi.org/10.5772/55257

47

Genome destabilization [150]

Loss of cell adhesion [137,139,179]

ATM kinase Cell cycle control, DNA

**Upregulation** *ATM*

*MMP-1, 2* Metallo proteinases

*CKS2* Cdc28/cdk1 protein

*PCNA* PCNA

*DSC1* Desmocollin-1

overwhelming body of information.

**5. Susceptibility genes**

**Down Regulation** *CDH1*

**Table 2.** Chromosomal aberrations involving important genes found in melanoma

#### **4. Roadway to melanoma**

Malignant melanomas arise from epidermal melanocytes or the melanocyte precursor cell which are derived from the neural crest and migrate to the skin and hair follicles [22]. Mela‐ noma initiation and progression is accompanied by a series of histological changes. The five distinct changes are: 1) nevus – benign lesion characterized by an increased number of nested melanocytes; 2) dysplastic nevus – which is characterized by random, discontinuous and atypical melanocytes; 3) radial-growth phase (RGP) melanoma where the cells acquire the ability to proliferate intraepidermally; 4) vertical growth phase (VGP) melanoma – character‐ ized by melanoma cells acquiring the ability to penetrate through the basement membrane (BM) into underlying dermis and subcutaneous tissue; and 5) metastatic melanoma – charac‐ terized by the spread of melanoma cells to other areas of the skin and other organs. The most critical event in melanoma progression is the RGP-VGP transition which involves the escape from keratinocyte mediated growth control. This is consistent with tumor thickness being a strong predictor of metastatic disease and adverse clinical outcome [23].


**Table 3.** Genetic expression signatures associated with the progression of melanomas [24]

Acquisition of somatic mutations in key regulatory genes is the driving force behind the initiation and progression of melanoma development. For the past few decades numerous research teams around the world have researched on melanoma genetics leading to an overwhelming body of information.
