Fig. 2

Genetic developmental model of acral melanoma: preliminary hypothesis. Most acral melanomas arises de novo, not in association with a preceding melanocytic nevus. The first event may be transformation of epidermal melanocytes though the initial driver gene(s), probably related to genomic instability, is not yet identified. Thereafter, the melanocytes acquire amplification (amp) of CCND1 and TERT and spread along the basal layer of the epidermis as the “field cells.” KIT mutations (mut) or amplification and BRAF/NRAS mutations may be also involved in the early developmental phase. With some unknown gene(s) aberration, the field cells become morphologically atypical melanocytes, and a histopathologically diagnosable lesion of acral melanoma in situ appears. In this phase, the melanocytes are dependent on some factor(s) from keratinocytes, preventing them to invade the dermis. Loss of CDKNA2 and/or aberration of other unknown gene(s) may contribute to transition from the in situ phase to the radial growth phase, making the cells independent of epidermal keratinocytes. In the following vertical growth phase, cell clones with a proliferative advantage and metastatic potential appear within the lesion. Other various genetic aberrations are responsible for the later progression phase