[Molecular heterogeneity of malignant melanomas]

Malignant melanomas make up a heterogeneous group of tumors characterized by particular genetic aberrations depending on their anatomic localization and UV exposure. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway is found in the majority of melanomas, with either somatic missense mutations of BRAF or, considerably more rarely, mutations of N-RAS. The loss of both products of the CDKN2A gene, proteins p16(ARF) and p14(INK4a), or amplification of microphthalmia-associated transcriptional factor (MITF) are also predisposing factors in the development of melanoma. BRAF mutations are observed mainly in melanomas on skin liable to intermittent UV exposure. Acral and mucosal melanomas, and also melanomas on skin damaged by chronic exposure to the sun are characterized by distinct patterns of chromosomal aberrations with frequent amplifications and alterations of the KIT gene, while BRAF mutations are rarely found in these sites. Uveal melanomas show recurrent chromosomal losses (1p, 3, 6q) and gains (6p, 8q), but mutations of BRAF are hardly ever found. So far, ancillary molecular studies are not regularly applied in the routine diagnostic procedures performed when malignant melanoma is suspected. In the future, however, the development of targeted molecular therapies will require that molecular pathological techniques are used to identify the melanoma patients who will most probably benefit from a particular therapy.