ENTRY H00038 Disease NAME Melanoma SUBGROUP Cutaneous malignant melanoma (CMM) SUPERGRP Solid tumor [DS:H02421] DESCRIPTION Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes. The only known environmental risk factor is exposure to ultraviolet (UV) light and in people with fair skin the risk is greatly increased. Melanoma pathogenesis is also driven by genetic factors. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Melanoma development has been shown to be strongly associated with inactivation of the p16INK4a/cyclin dependent kinases 4 and 6/retinoblastoma protein (p16INK4a/CDK4,6/pRb) and p14ARF/human double minute 2/p53 (p14ARF/HMD2/p53) tumor suppressor pathways. MITF and TP53 are implicated in further melanoma progression. CATEGORY Cancer BRITE Human diseases in ICD-11 classification [BR:br08403] 02 Neoplasms Malignant neoplasms, except primary neoplasms of lymphoid, haematopoietic, central nervous system or related tissues Malignant neoplasms, stated or presumed to be primary, of specified sites, except of lymphoid, haematopoietic, central nervous system or related tissues Malignant neoplasms of skin 2C30 Melanoma of skin H00038 Melanoma Pathway-based classification of diseases [BR:br08402] Replication and repair nt06510 Telomere length regulation H00038 Melanoma nt06506 Double-strand break repair H00038 Melanoma Signal transduction nt06526 MAPK signaling H00038 Melanoma Tumor markers [br08442.html] H00038 Cancer-associated carbohydrates [br08441.html] H00038 DIS_PATHWAY hsa05218 Melanoma NETWORK nt06268 Melanoma nt06506(H00038) Double-strand break repair nt06510(H00038) Telomere length regulation GENE (CMM2) CDKN2A [HSA:1029] [KO:K06621] (CMM3) CDK4 [HSA:1019] [KO:K02089] (CMM5) MC1R [HSA:4157] [KO:K04199] (CMM6) XRCC3 [HSA:7517] [KO:K10880] (CMM8) MITF (amplification) [HSA:4286] [KO:K09455] (CMM9) TERT [HSA:7015] [KO:K11126] (CMM10) POT1 [HSA:25913] [KO:K11109] BRAF [HSA:673] [KO:K04365] STK11 [HSA:6794] [KO:K07298] NRAS [HSA:4893] [KO:K07828] PTEN [HSA:5728] [KO:K01110] TP53 [HSA:7157] [KO:K04451] DRUG Dacarbazine [DR:D00288] Vemurafenib [DR:D09996] (BRAF mutation positive) Dabrafenib mesylate [DR:D10104] (BRAF mutation positive) Encorafenib [DR:D11053] (BRAF mutation positive) Trametinib dimethyl sulfoxide [DR:D10176] (BRAF mutation positive) Cobimetinib fumarate [DR:D10615] (BRAF mutation positive) Binimetinib [DR:D10604] (BRAF mutation positive) Nivolumab [DR:D10316] Pembrolizumab [DR:D10574] Ipilimumab [DR:D04603] Nivolumab and relatlimab [DR:D12334] Talimogene laherparepvec [DR:D09966] Lifileucel [DR:D12833] (BRAF V600 mutation positive) Tebentafusp [DR:D12296] (HLA-A*02:01-positive) Interferon alfa-2b [DR:D02745] Peginterferon alfa-2b [DR:D02748] Aldesleukin [DR:D00748] DBLINKS ICD-11: 2C30 ICD-10: C43 MeSH: D008545 OMIM: 613099 613972 615134 155600 155601 609048 614456 615848 REFERENCE PMID:16822996 AUTHORS Miller AJ, Mihm MC Jr. TITLE Melanoma. JOURNAL N Engl J Med 355:51-65 (2006) DOI:10.1056/NEJMra052166 REFERENCE PMID:15468170 AUTHORS Tsai KY, Tsao H. TITLE The genetics of skin cancer. JOURNAL Am J Med Genet C Semin Med Genet 131C:82-92 (2004) DOI:10.1002/ajmg.c.30037 REFERENCE PMID:17492760 (CDKN2A) AUTHORS Kannengiesser C, Dalle S, Leccia MT, Avril MF, Bonadona V, Chompret A, Lasset C, Leroux D, Thomas L, Lesueur F, Lenoir G, Sarasin A, Bressac-de Paillerets B TITLE New founder germline mutations of CDKN2A in melanoma-prone families and multiple primary melanoma development in a patient receiving levodopa treatment. JOURNAL Genes Chromosomes Cancer 46:751-60 (2007) DOI:10.1002/gcc.20461 REFERENCE PMID:15880589 (CDK4) AUTHORS Molven A, Grimstvedt MB, Steine SJ, Harland M, Avril MF, Hayward NK, Akslen LA TITLE A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation. JOURNAL Genes Chromosomes Cancer 44:10-8 (2005) DOI:10.1002/gcc.20202 REFERENCE PMID:16809487 (MC1R) AUTHORS Landi MT, Bauer J, Pfeiffer RM, Elder DE, Hulley B, Minghetti P, Calista D, Kanetsky PA, Pinkel D, Bastian BC TITLE MC1R germline variants confer risk for BRAF-mutant melanoma. JOURNAL Science 313:521-2 (2006) DOI:10.1126/science.1127515 REFERENCE PMID:11059748 (XRCC3) AUTHORS Winsey SL, Haldar NA, Marsh HP, Bunce M, Marshall SE, Harris AL, Wojnarowska F, Welsh KI TITLE A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. JOURNAL Cancer Res 60:5612-6 (2000) REFERENCE PMID:22012259 (MITF) AUTHORS Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, Dessen P, d'Hayer B, Mohamdi H, Remenieras A, Maubec E, de la Fouchardiere A, Molinie V, Vabres P, Dalle S, Poulalhon N, Martin-Denavit T, Thomas L, Andry-Benzaquen P, Dupin N, Boitier F, Rossi A, Perrot JL, Labeille B, Robert C, Escudier B, Caron O, Brugieres L, Saule S, Gardie B, Gad S, Richard S, Couturier J, Teh BT, Ghiorzo P, Pastorino L, Puig S, Badenas C, Olsson H, Ingvar C, Rouleau E, Lidereau R, Bahadoran P, Vielh P, Corda E, Blanche H, Zelenika D, Galan P, Aubin F, Bachollet B, Becuwe C, Berthet P, Bignon YJ, Bonadona V, Bonafe JL, Bonnet-Dupeyron MN, Cambazard F, Chevrant-Breton J, Coupier I, Dalac S, Demange L, d'Incan M, Dugast C, Faivre L, Vincent-Fetita L, Gauthier-Villars M, Gilbert B, Grange F, Grob JJ, Humbert P, Janin N, Joly P, Kerob D, Lasset C, Leroux D, Levang J, Limacher JM, Livideanu C, Longy M, Lortholary A, Stoppa-Lyonnet D, Mansard S, Mansuy L, Marrou K, Mateus C, Maugard C, Meyer N, Nogues C, Souteyrand P, Venat-Bouvet L, Zattara H, Chaudru V, Lenoir GM, Lathrop M, Davidson I, Avril MF, Demenais F, Ballotti R, Bressac-de Paillerets B TITLE A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. JOURNAL Nature 480:94-8 (2011) DOI:10.1038/nature10539 REFERENCE PMID:23348506 (TERT) AUTHORS Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA TITLE Highly recurrent TERT promoter mutations in human melanoma. JOURNAL Science 339:957-9 (2013) DOI:10.1126/science.1229259 REFERENCE PMID:24686849 (POT1) AUTHORS Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, Pooley KA, Pritchard AL, Tiffen JC, Petljak M, Palmer JM, Symmons J, Johansson P, Stark MS, Gartside MG, Snowden H, Montgomery GW, Martin NG, Liu JZ, Choi J, Makowski M, Brown KM, Dunning AM, Keane TM, Lopez-Otin C, Gruis NA, Hayward NK, Bishop DT, Newton-Bishop JA, Adams DJ TITLE POT1 loss-of-function variants predispose to familial melanoma. JOURNAL Nat Genet 46:478-481 (2014) DOI:10.1038/ng.2947 REFERENCE PMID:15785879 (BRAF) AUTHORS Gray-Schopfer VC, da Rocha Dias S, Marais R. TITLE The role of B-RAF in melanoma. JOURNAL Cancer Metastasis Rev 24:165-83 (2005) DOI:10.1007/s10555-005-5865-1 REFERENCE PMID:10208439 (STK11) AUTHORS Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J TITLE Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma. JOURNAL Oncogene 18:1777-80 (1999) DOI:10.1038/sj.onc.1202486 REFERENCE PMID:19037234 (NRAS BRAF) AUTHORS Greene VR, Johnson MM, Grimm EA, Ellerhorst JA TITLE Frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase in cutaneous melanoma. JOURNAL J Invest Dermatol 129:1483-8 (2009) DOI:10.1038/jid.2008.374 REFERENCE PMID:10651986 (PTEN) AUTHORS Birck A, Ahrenkiel V, Zeuthen J, Hou-Jensen K, Guldberg P TITLE Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. JOURNAL J Invest Dermatol 114:277-80 (2000) DOI:10.1046/j.1523-1747.2000.00877.x ///