Melanoma is a common cancer in the Western world with an increasing incidence. Sun exposure is still considered to be the major risk factor for melanoma. The prognosis of patients with malignant (advanced-stage) melanoma differs widely between countries, but public campaigns advocating early detection have led to significant reductions in mortality rates. As well as sun exposure, distinct genetic alterations have been identified as associated with melanoma. For example, families with melanoma who have germline mutations in CDKN2A are well known, whereas the vast majority of sporadic melanomas have mutations in the mitogen-activated protein kinase cascade, which is the pathway with the highest oncogenic and therapeutic relevance for this disease. BRAF and NRAS mutations are typically found in cutaneous melanomas, whereas KIT mutations are predominantly observed in mucosal and acral melanomas. GNAQ and GNA11 mutations prevail in uveal melanomas. Additionally, the PI3K–AKT–PTEN pathway and the immune checkpoint pathways are important. The finding that programmed cell death protein 1 ligand 1 (PDL1) and PDL2 are expressed by melanoma cells, T cells, B cells and natural killer cells led to the recent development of programmed cell death protein 1 (PD1)-specific antibodies (for example, nivolumab and pembrolizumab). Alongside other new drugs — namely, BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) — these agents are very promising and have been shown to significantly improve prognosis for patients with advanced-stage metastatic disease. Early signs are apparent that these new treatment modalities are also improving long-term clinical benefit and the quality of life of patients. This Primer summarizes the current understanding of melanoma, from mechanistic insights to clinical progress. For an illustrated summary of this Primer, visit: http://go.nature.com/vX2N9s
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This work was not supported by a third party.
D.S. and A. Hauschild declare an association with the following companies: Amgen, Bristol–Myers Squibb, Genentech, GlaxoSmithKline, Merck/MSD, Novartis, Pfizer, Boehringer Ingelheim and Roche. C.G. declares personal fees from Amgen, Merck/MSD and Novartis, and declares grants and personal fees from Bristol–Myers Squibb, GlaxoSmithKline and Roche outside of the submitted work. A. Roesch has received travel grants and honoraria from Roche and TEVA, and research grants from Novartis. M.A.M. has received honoraria from Next Meeting Generation for speaking on the topic of dermoscopy at the American Dermoscopy Meeting. A. Halpern serves as a consultant to Caliber Imaging and Diagnostics, Canfield Scientific, DermTech and SciBase AB, and serves on the data safety and monitoring board of Quintiles and Janssen Research and Development LLC. J.-J.G. has received fees for advisory boards and lectures from Amgen, GlaxoSmithKline, MSD, Novartis and Roche, and has received research grants from Bristol–Myers Squibb and Roche. J.E.G. serves on the global advisory board for Merck. A. Ribas has served as consultant for Amgen, Astellas, Genentech-Roche, GlaxoSmithKline, Merck, Novartis and Pierre Fabre, and serves on the scientific advisory board and has stock options for Compugen, Flexus Biosciences and Kite Pharma. G.M. has received consulting income from Provectus, and has received research support from Celgene and Pfizer. M.H. and D.E.F. declare no competing interests.
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