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Melanoma is a type of skin cancer which develops from melanocytes. Globally, it is the most dangerous and deadliest form of skin cancer mainly caused by the exposure to ultraviolet (UV) radiation from either the sun or tanning beds. Additionally, the incidence and mortality of melanoma are largely influenced by age and sex differences. According to America Cancer Society, although invasive melanoma accounts for only 1% of all skin cancer cases, it represents the vast majority of skin cancer deaths.
Melanocytes are pigment-producing cells found in the upper layer of skin that produce melanin. Basically, there are two types of melanin: the black/brown pigment eumelanin and a red/yellow pigment pheomelanin, where the ratio of two is relatively constant in all skin types, determining the skin color. When skin is exposed to UV radiation, eumelanin can protect the skin better from this damage, whereas pheomelanin not only provide less shield against radiation but the production of it produces carcinogens. It has been proved that pheomelanin can produce more ultraviolet-A-induced reactive oxidative species (ROS), causing greater DNA damage related with UV radiation.
Approximately 5-12% of melanomas are hereditary. CDKN2A is a mutation commonly found in melanoma syndromes that defects the proteins p14ARF and p16INK4A, which are important tumor suppressors. Besides, various oncogenic signaling pathways are misregulated in melanoma, including those involved in proliferation (BRAF, NRAS, and NF1), growth and metabolism (PTEN and KIT), replicative lifespan (TERT), cell identity (ARID2), resistance to apoptosis (TP63), and cell cycle control (CDKN2A).
Fig.1. Oncogenic pathways misregulated in melanoma
Melanoma is usually curable when detected and treated early. However, once melanoma has spread deeper into other parts of the body, it becomes hard to treat and is likely to cause death. To improve the detection and diagnosis of melanoma, non-invasive imaging technology and more quantitative techniques including fluorescence in situ hybridization (FISH), sequencing, mass spectrometry (MS) and immunohistochemistry (IHC) have been used more frequently nowadays. Additionally, a wide range of biomarkers are also applied to melanoma prognosis. Ki-67 and PHH3 as proliferation indicators are widely used in melanoma prognosis. Lactate dehydrogenase (LDH) which can be detected in patient serum has been regarded as the strongest independent prognostic indicators for malignant melanoma. However, it is relatively difficult to diagnose melanoma only according a single biomarker because of the diversity of this disease. Therefore, multiple biomarkers are used to overcome the drawbacks of the individual biomarkers, and to this end, research into exploring new melanoma indicators is ongoing.
Surgical removal of the tumor is the primary treatment for localized melanoma, although metastatic tumors can occur sometimes. For patients with metastatic disease, chemotherapies are essential. Additionally, with the development of targeted therapies and immunotherapies such as BRAF, CTLA4 and PD1 inhibitors, the treatment of metastatic melanoma has greatly improved in recent years. Although the problems with secondary resistance have been discovered, researchers have been making effort to develop new targets and drug combinations to achieve a better therapeutic effect.
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