The individual involvement of the products of the eight studied genes (shown in red colour) in the (a) RAS/RAF/MEK/MAPK, (b) PI3K/AKT, and (c) GNAQ/11 signalling transduction pathways. BRAF (shown in dark red colour) was the only gene found mutated in a single patient in our series. All three members of the RAS family of GTPases, that is, the HRAS, KRAS, and NRAS, function as regulated binary switches and, following growth factor stimulation via the receptor tyrosine kinase (RTK), bind and activate downstream effectors, mainly BRAF and PI3K, leading sequentially to the activation of the ERK and AKT kinases, operating in the two major signal transduction pathways, respectively. Additional pathways, such as the apoptosis pathway and the CDK pathway leading to cell cycle progression, can be further activated from these downstream effectors of the two major pathways. Upstream of RAS and PI3K, c-KIT can be also mutated or amplified in melanoma and in turn activate the downstream effectors of the two major pathways. An alternative pathway via the endothelin receptor (ETR), involving two heterotrimeric G-α-proteins, that is, GNAQ and GNA11, can also activate the BRAF/MEK/MAPK/ERK pathway and appears to be important for both normal melanocyte development and melanoma formation. Finally, MITF plays also an essential role in melanocyte-specific transcription, exhibiting multiple regulatory functions. mTOR, mammalian target of rapamycin; MITF, microphthalmia-associated transcription factor; TFs, transcription factors.