Where<unk>  is most likely to develop Molecular basis for<unk>  cell motility: actin-rich podosomes (yellow), along with cell nuclei (blue), actin (red), and an actin regulator (green). The earliest stage of<unk>  starts when melanocytes begin out-of-control growth. Melanocytes are found between the outer layer of the skin (the epidermis) and the next layer (the dermis). This early stage of the disease is called the radial growth phase, when the tumor is less than 1 mm thick, and spreads at the level of the basal epidermis. Because the cancer cells have not yet reached the blood vessels deeper in the skin, it is very unlikely that this early-stage<unk>  will spread to other parts of the body. If the<unk>  is detected at this stage, then it can usually be completely removed with surgery. When the tumor cells start to move in a different direction – vertically up into the epidermis and into the papillary dermis – cell behaviour changes dramatically. The next step in the evolution is the invasive radial growth phase, in which individual cells start to acquire invasive potential. From this point on,<unk>  is capable of spreading. The Breslow's depth of the lesion is usually less than , while the Clark level is usually 2. The vertical growth phase (VGP) following is invasive<unk> . The tumor becomes able to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than , and the tumor involves the deeper parts of the dermis. The host elicits an immunological reaction against the tumor during the VGP, which is judged by the presence and activity of the tumor infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary tumor; this is called regression, which is the latest stage of development. In certain cases, the primary tumor is completely destroyed and only the metastatic tumor is discovered. About 40% of human<unk> s contain activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the Raf to MAP kinase pathway. An insult common to most cancers is damage to DNA. UVA light mainly causes thymine dimers. UVA also produces reactive oxygen species and these inflict other DNA damage, primarily single-strand breaks, oxidized pyrimidines and the oxidized purine 8-oxoguanine (a mutagenic DNA change) at 1/10th, 1/10th, and 1/3rd the frequencies of UVA-induced thymine dimers, respectively. If unrepaired, CPD photoproducts can lead to mutations by inaccurate translesion synthesis during DNA replication or repair. The most frequent mutations due to inaccurate synthesis past CPDs are cytosine to thymine (C>T) or CC>TT transition mutations. These are commonly referred to as UV fingerprint mutations, as they are the most specific mutation caused by UV, being frequently found in sun-exposed skin, but rarely found in internal organs. Errors in DNA repair of UV photoproducts, or inaccurate synthesis past these photoproducts, can also lead to deletions, insertions, and chromosomal translocations. The entire genomes of 25<unk> s were sequenced. On average, about 80,000 mutated bases (mostly C>T transitions) and about 100 structural rearrangements were found per<unk>  genome. This is much higher than the roughly 70 mutations across generations (parent to child). Among the 25<unk> s, about 6,000 protein-coding genes had missense, nonsense, or splice site mutations. The transcriptomes of over 100<unk> s has also been sequenced and analyzed. Almost 70% of all human protein-coding genes are expressed in<unk> . Most of these genes are also expressed in other normal and cancer tissues, with some 200 genes showing a more specific expression pattern in<unk>  compared to other forms of cancer. Examples of<unk>  specific genes are tyrosinase, MLANA, and PMEL. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. This strong mutagenic factor makes cutaneous<unk>  the tumor type with the highest number of mutations. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of activating transcription factor in the nucleus of<unk>  cells are associated with increased metastatic activity of<unk>  cells; studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer progression. Cancer stem cells may also be involved. Gene mutations Large-scale studies, such as The Cancer Genome Atlas, have characterized recurrent somatic alterations likely driving initiation and development of cutaneous<unk> . The most frequent mutation occurs in the 600th codon of BRAF (50% of cases). BRAF is normally involved in cell growth, and this specific mutation renders the protein constitutively active and independent of normal physiological regulation, thus fostering tumor growth. RAS genes (NRAS, HRAS and KRAS) are also recurrently mutated (30% of TCGA cases) and mutations in the 61st or 12th codons trigger oncogenic activity. Loss-of-function mutations often affect tumor suppressor genes such as NF1, TP53 and CDKN2A. Other oncogenic alterations include fusions involving various kinases such as BRAF, RAF1, ALK, RET, ROS1, NTRK1., NTRK3 and MET BRAF, RAS, and NF1 mutations and kinase fusions are remarkably mutually exclusive, as they occur in different subsets of patients. Assessment of mutation status can, therefore, improve patient stratification and inform targeted therapy with specific inhibitors. In some cases (3-7%) mutated versions of BRAF and NRAS undergo copy-number amplification. Metastasis The research done by Sarna's team proved that heavily pigmented<unk>  cells have Young's modulus about 4.93, when in non-pigmented ones it was only 0.98. In another experiment they found that elasticity of<unk>  cells is important for its metastasis and growth: non-pigmented tumors were bigger than pigmented and it was much easier for them to spread. They shown that there are both pigmented and non-pigmented cells in<unk>  tumors, so that they can both be drug-resistant and metastatic.
Melanoma
Blue nevus
Pseudomelanoma
Seborrheic keratosis
Xanthoma
Lentigo
Nodular melanoma
Dermatofibroma