**5. Susceptibility genes**

**Candidate Gene Protein**

**Gene losses** *PTEN*

46 Highlights in Skin Cancer

**Gene amplification** *BRAF*

**4. Roadway to melanoma**

**Location on**

*CDKN2A* p16Ink4a/p14Arf 9p Primary & metastatic [135,136]

*ITGB3BP* Beta-3-endonexin 1p31 Uveal [138]

*CCND1* cyclinD1 11q13 Acral [136]

*CDK4* cdk4 12q14 Acral & mucosal [136]

*CDH2* N-cadherin 18q Uveal & metastatic [137,139]

*MITF* Mitf 3p14 Cutaneous, metastatic [142,143]

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

*c-MYC* c-myc 8q23 Ocular, primary &

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

strong predictor of metastatic disease and adverse clinical outcome [23].

**chromosome Stage of melanoma References**

metastatic

[135,137,140,141]

Pten 10q Primary & metastatic [135,136,137]

Braf 7q21.3 Cutaneous [135]

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 cycle progression arrest through G1-S; while p14 favors apoptosis and blocks oncogenic transformation by stabilizing p53 levels through the inhibition of Mdm2-mediated p53 ubiquitination [27,28,29,30]. Loss of p16 promotes hyper-phosphorylation of pRb resulting in its inactivation while the loss of p14 inactivates p53 — leading to unrestricted cell cycle progression. Germline mutations in CDKN2A have been found in 40% of families with 3 or more family members affected by melanoma [31]. Not all individuals carrying germ‐ line CDKN2A mutations develop mutations. Individuals with large numbers of pigment lesions or nevi have familial atypical mole-melanoma syndrome (FAMS) are associated with increased risk to developing melanoma [32,33].

Ras mutations being relatively rare [49,50]. Constitutive activation of Ras-Raf-Mek-Erk cascade has been shown to contribute to tumorigenesis by inhibiting apoptosis and increasing cell proliferation, tumor invasion and metastasis. Activated Erk plays a pivotal role in cell proliferation by controlling the G1- to S-phase transition by negative regula‐ tion of p27 inhibition and upregulation of c-myc activity [51,52]. Inhibition of Erk activity is associated with G1 cell cycle arrest by upregulation of p21 and reduced phosphoryla‐ tion [52]. Activated Erk is also known to stimulate cell proliferation by increasing the transcription and stability of c-Jun which is mediated by CREB (cyclic adenosine monophos‐ phate responsive element-binding) and Gsk-3β (glycogen synthase kinase-3beta) respective‐ ly [53]. Erk is also believed to increase proliferation by inhibiting differentiation. Constitutively active Erk limits differentiation in melanoma by targeting MITF (micro‐ phthalmia-associated transcription factor) for degradation [54,55,56]. The activated Erk pathway enhances melanoma specific survival by differentially regulating RSK-mediated phosphorylation and inactivation of the pro-apoptotic protein Bad [57] and inhibiting Jak-

An Overview of Important Genetic Aspects in Melanoma

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

49

Erk signaling also contributes towards tumor invasion and metastasis by regulating the expression of integrin and matrix metalloproteinases (MMPs). Activated Ras-Mek-Erk

The PI3K/Akt pathway is activated in various cancers, mostly on accont of mutations in tumor suppressor PTEN (phosphatase and tensin homolog) [62]. In melanoma, los of PTEN on chromosome 10q 23-24 was first reported by Parmiter et al [63]. The PTEN gene encodes a phosphatase that degrades products of PI3K by dephosphorylating phosphatidylinositol 3,4,5 triphosphate and phosphatidylinositol 3,4-biphosphate at 3 positions [64]. Loss of PTEN increases AKT phosphorylation and activity leading to increased mitogenic signaling and decreased apoptosis [65]. Various studies suggest that 30-40% of melanoma cell lines and 5-15% of uncultured melanoma specimens carry inactivating mutations or homozygous deletions of

Pten encodes a negative regulator of extracellular growth signals that are transcended via PI3K-Akt pathway. Akt/protein kinase B (PKB), a serine-threonine kinase, is a core component of the PI3K signaling cascade and is activated through the phosphorylation of Ser 473/474 and Thr 308/309 [68,69]. Activated Akt regulates a network of factors that control cell proliferation and survival and this pathway is hyperactive in most metastatic melanomas [70,71,72]. Akt activates the transcription of a wide variety of genes involved in a wide range of cellular activities – those involved in immune activation, cell proliferation, apoptosis and cell survival [69]. Several studies have documented Akt activation in melanoma. Dai et al undertook a 292 sample study of pAkt levels using tissue microarray & immunohistochemistry strategies and identified strong pAkt expression in 17%, 43%, 49% and 77% of the biopsies in normal nevi, dysplastic nevi, primary melanoma and melanoma metastasis respectively. An important cell

Stat pathway [58].

Pten [63,66,67].

**8. The PI3K/Akt pathway**

pathway drives the production of MMP1 [59,60,61].

The other melanoma susceptibility gene, CDK4 is located at chromosome 12q14 [34,35,36]. Mutations in CDK4 abrogate binding of cdk4 to p16 have been associated with melanoma pathogenesis [32]. This is evidence that links the entire p16Ink4A-cdk4/cdk6-pRb pathway to melanoma indicating that hereditary retinoblastoma patients with germline inactivation of retinoblastoma (Rb1) are predisposed to melanoma [37,38].
