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 [BR:br08402]
Cancers
  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]
H00038
Cancer-associated carbohydrates [br08441.html]
H00038

Pathway

hsa05218

Melanoma

Related
pathway

hsa05225

Hepatocellular carcinoma

Network

nt06268 Melanoma
nt06510 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]
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

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

DISEASE: Melanoma