Abstract
Melanocytes are located in various parts of the human body, such as the skin and the eye. Their transformation leads to melanoma, an aggressive and deadly neoplasm. Cutaneous and uveal melanomas show different characteristics, including significant differences in genetic alterations, metastatic sites and therapeutic response. In recent decades, great efforts have been made to obtain a more comprehensive understanding of genetics, genomics and molecular changes, enabling the identification of key cellular processes and signaling pathways in melanomas. Major breakthroughs were realized in the treatment of metastatic cutaneous melanoma, but most patients relapse. Currently, there is no approved systemic treatment for metastatic uveal melanoma. Thus, these two different cancers are in therapeutic need to overcome treatment failure and improve patient prognosis. In this review we discuss on one hand the mutation of MITF, the master gene of melanocyte homeostasis, which we identified as a new melanoma predisposition gene in cutaneous melanoma, and on the other hand the recent findings of intratumor heterogeneity and characterization of cell sub-populations in primary uveal melanomas. These studies offer new tools for early detection and therapeutic targets.
Highlights
Cutaneous malignant melanoma is a deadly form of skin cancer which accounts for 1.6% of all diagnosed cancers
In approximately 10% of cases, cutaneous melanomas occur in a familial context, and are associated with rare highly penetrant germline mutations in cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A), a gene that codes for two different tumor suppressors (p16INK4a and p14ARF ), CDK4 and BRCA1-associated protein 1 (BAP1)
In contrast to cutaneous melanomas, which is driven by mutation in BRAF or NRAS and to a lesser extent in NF1, the primary oncogenic driver of choroidal melanoma is a mutant form of the heterotrimeric G-protein alpha subunit GNAQ or its closely related homolog GNA11 [34]
Summary
Melanocytes derive from the neural crest as undifferentiated cells, called melanoblasts, which migrate to various parts of the human body, such as the skin, eyes, meninges, heart, and cochlea. Melanocyte physiological function is to synthesize melanin. Two melanin types are produced, the brown/black pigment eumelanin and the orange/yellow pigment pheomelanin. The proportion of these two types of melanin defines the variation in skin, hair and iris colour: the ratio of eumelanin/pheomelanin is significantly greater in both dark brown skin and eyes than in pale skin and eyes with light-colored irises [1, 2]. Prevalence and incidence of cutaneous and uveal melanomas vary between ethnic groups and geographical areas. The people with fair eyes and fair skin and those with an inability to tan are more predisposed to cutaneous and ocular melanomas [5]
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