Abstract
Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.
Highlights
Sunlight exposure represents the most common environmental risk factor in the development of skin cancer, including melanoma
Particular attention was focused on analyzing the mutational spectrum of pan-negative melanomas, which included: (i) less-frequent mutations of B Rapidly Accelerated Fibrosarcoma (BRAF), Neuroblastoma Rapidly Accelerated Sarcoma (NRAS), KIT, GNA11, and GNAQ; (ii) 12 genes were found to be mutated in “pan negative” tumors at a frequency significantly higher than that observed in driver gene-positive tumors, and these genes include Anaplastic Lymphoma Kinase (ALK), STK 31, DGKI, RAC1, EPHA4, ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR [57]
According to the findings observed in this important study, some conclusions were reached: (a) at the level of precursor lesions, the initial mutagenic events triggering the neoplastic transformation are represented by a number of mutations leading to activation of the mitogen-activated protein kinase (MAPK) pathway; (b) at an intermediate stage of tumor progression, NRAS and additional driver mutations are observed: interestingly, in these tumor lesions TERT promoter mutations are very frequent (77% of cases), suggesting that the selection of mechanisms precluding cell senescence are an early event during melanoma progression; (c) biallelic inactivation of CDKN2A and Phosphatase and Tensin Homolog (PTEN) and TP53 mutations were found only in advanced melanoma lesions (Figure 2) [97]
Summary
Sunlight exposure represents the most common environmental risk factor in the development of skin cancer, including melanoma. Even before exposure to UV radiation, 50% of red mice developed melanomas after crossing with mice expressing the melanoma oncogene BRAFV600E [1]; it is important to note that this phenomenon was not observed among albino mice, indicating that it is the presence of pheomelanin and not the absence of eumelanin which favors melanoma development [1] This tumor-promoting effect of pheomelanin seems to be related to the capacity of this melanin type to spontaneously induce reactive oxygen species (ROS) production, even in the absence of UV exposure [1]. A recent study suggested that the mechanisms through which UVA (320–400 nm) and UVB (280–320 nm) induce melanoma development is different: UVA induction of melanoma requires the presence of melanin pigment and is associated with DNA oxidative damage, while UVB initiates melanoma in a pigment-independent manner associated with direct UVB DNA damage [2]
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