title: Melanoma.
abstract: 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.
authors.affiliation: Department of Dermatology, University Duisburg-Essen, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|Department of Dermatology, University Tübingen, Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.affiliation: Department of Dermatology and Skin Cancers, APHM Timone Hospital Aix-Marseille University, Marseille, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
authors.affiliation: Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Halpern
authors.affiliation: Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Marchetti
authors.affiliation: Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: McArthur
authors.affiliation: Departments of Medicine, Surgery, and Medical and Molecular Pharmacology, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Department of Dermatology, University Duisburg-Essen, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Roesch
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D060890:B7-H1 Antigen / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000209:etiology / Q000235:genetics / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D013472:Sunlight / Q000009:adverse effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D008565:Membrane Proteins; C094601:PDCD2 protein, human; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D043802:GTP-Binding Protein alpha Subunits, Gq-G11