KEGG   DISEASE: Melanoma
H00038                      Disease                                
Cutaneous malignant melanoma (CMM)
Solid tumor [DS:H02421]
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.
Human diseases [BR:br08402]
  Skin cancers
   H00038  Melanoma
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
Tumor markers [br08442.html]
Cancer-associated carbohydrates [br08441.html]
hsa05218  Melanoma
hsa05200  Pathways in cancer
hsa05225  Hepatocellular carcinoma
nt06268  Melanoma
(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]
8-Methoxypsoralen (Methoxsalen) plus ultraviolet A radiation [CPD:C01864]
Solar radiation
*Benzo[a]pyrene [CPD:C07535]
*Chimney sweeping
*Mineral oils, untreated and mildly treated
*: Although this is a risk factor for skin cancer in general, the strength of association with different histological tumor types is not well understood.
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]
Talimogene laherparepvec [DR:D09966]
Interferon alfa-2b [DR:D02745]
Peginterferon alfa-2b [DR:D02748]
Aldesleukin [DR:D00748]
Tebentafusp [DR:D12296] (HLA-A*02:01-positive)
Nivolumab and relatlimab [DR:D12334]
Other DBs
ICD-11: 2C30
ICD-10: C43
MeSH: D008545
OMIM: 613099 613972 615134 155600 155601 609048 614456 615848
Miller AJ, Mihm MC Jr.
N Engl J Med 355:51-65 (2006)
Tsai KY, Tsao H.
The genetics of skin cancer.
Am J Med Genet C Semin Med Genet 131C:82-92 (2004)
PMID:17492760 (CDKN2A)
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
New founder germline mutations of CDKN2A in melanoma-prone families and multiple primary melanoma development in a patient receiving levodopa treatment.
Genes Chromosomes Cancer 46:751-60 (2007)
PMID:15880589 (CDK4)
Molven A, Grimstvedt MB, Steine SJ, Harland M, Avril MF, Hayward NK, Akslen LA
A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation.
Genes Chromosomes Cancer 44:10-8 (2005)
PMID:16809487 (MC1R)
Landi MT, Bauer J, Pfeiffer RM, Elder DE, Hulley B, Minghetti P, Calista D, Kanetsky PA, Pinkel D, Bastian BC
MC1R germline variants confer risk for BRAF-mutant melanoma.
Science 313:521-2 (2006)
PMID:11059748 (XRCC3)
Winsey SL, Haldar NA, Marsh HP, Bunce M, Marshall SE, Harris AL, Wojnarowska F, Welsh KI
A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer.
Cancer Res 60:5612-6 (2000)
PMID:22012259 (MITF)
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
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.
Nature 480:94-8 (2011)
PMID:23348506 (TERT)
Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA
Highly recurrent TERT promoter mutations in human melanoma.
Science 339:957-9 (2013)
PMID:24686849 (POT1)
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
POT1 loss-of-function variants predispose to familial melanoma.
Nat Genet 46:478-481 (2014)
PMID:15785879 (BRAF)
Gray-Schopfer VC, da Rocha Dias S, Marais R.
The role of B-RAF in melanoma.
Cancer Metastasis Rev 24:165-83 (2005)
PMID:10208439 (STK11)
Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J
Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma.
Oncogene 18:1777-80 (1999)
PMID:19037234 (NRAS BRAF)
Greene VR, Johnson MM, Grimm EA, Ellerhorst JA
Frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase in cutaneous melanoma.
J Invest Dermatol 129:1483-8 (2009)
PMID:10651986 (PTEN)
Birck A, Ahrenkiel V, Zeuthen J, Hou-Jensen K, Guldberg P
Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies.
J Invest Dermatol 114:277-80 (2000)

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