Entry Name Melanoma - Homo sapiens (human)
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.
Class Human Diseases; Cancer: specific typesBRITE hierarchy
Pathway map Ortholog table Network Element N00012 Mutation-activated KRAS/NRAS to ERK signaling pathway
N00013 Mutation-activated BRAF to ERK signaling pathway
N00032 Mutation-activated KRAS/NRAS to PI3K signaling pathway
N00051 Deleted PTEN to PI3K signaling pathway
N00052 Mutation-inactivated PTEN to PI3K signaling pathway
N00067 Deleted p14(ARF) to p21-cell cycle G1/S
N00070 Mutation-inactivated p16(INK4a) to p16-cell cycle G1/S
N00071 Deleted p16(INK4a) to p16-cell cycle G1/S
N00073 Mutation-activated CDK4 to cell cycle G1/S
N00076 Mutation-inactivated p14(ARF) to p21-cell cycle G1/S
N00115 Mutation-inactivated TP53 to transcription
Disease Drug D09996 Vemurafenib (JAN/USAN/INN)
D10104 Dabrafenib mesylate (USAN)
D10176 Trametinib dimethyl sulfoxide (JAN/USAN)
D10604 Binimetinib (JAN/USAN/INN)
D10615 Cobimetinib fumarate (USAN)
D11053 Encorafenib (JAN/USAN/INN)
Organism Homo sapiens (human) [GN:
hsa ]
Gene 8822 FGF17; fibroblast growth factor 17 [KO:K04358 ]
2255 FGF10; fibroblast growth factor 10 [KO:K04358 ]
8823 FGF16; fibroblast growth factor 16 [KO:K04358 ]
8817 FGF18; fibroblast growth factor 18 [KO:K04358 ]
9965 FGF19; fibroblast growth factor 19 [KO:K22603 ]
8074 FGF23; fibroblast growth factor 23 [KO:K22428 ]
3479 IGF1; insulin like growth factor 1 [KO:K05459 ]
5154 PDGFA; platelet derived growth factor subunit A [KO:K04359 ]
5155 PDGFB; platelet derived growth factor subunit B [KO:K17386 ]
56034 PDGFC; platelet derived growth factor C [KO:K05450 ]
80310 PDGFD; platelet derived growth factor D [KO:K05450 ]
3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833 ]
3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827 ]
4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
572 BAD; BCL2 associated agonist of cell death [KO:K02158 ]
1029 CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621 ]
1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625 ]
5925 RB1; RB transcriptional corepressor 1 [KO:K06618 ]
1647 GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402 ]
4616 GADD45B; growth arrest and DNA damage inducible beta [KO:K04402 ]
10912 GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402 ]
581 BAX; BCL2 associated X, apoptosis regulator [KO:K02159 ]
578 BAK1; BCL2 antagonist/killer 1 [KO:K14021 ]
1643 DDB2; damage specific DNA binding protein 2 [KO:K10140 ]
4286 MITF; melanocyte inducing transcription factor [KO:K09455 ]
Compound C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Miller AJ, Mihm MC Jr.
Title Melanoma.
Journal Reference Authors Chin L.
Title The genetics of malignant melanoma: lessons from mouse and man.
Journal Reference Authors Takata M, Saida T.
Title Genetic alterations in melanocytic tumors.
Journal Reference Authors Chudnovsky Y, Khavari PA, Adams AE.
Title Melanoma genetics and the development of rational therapeutics.
Journal Reference Authors Merlino G.
Title Cancer biology: the weakest link?
Journal Reference Authors Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR.
Title Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.
Journal Reference Authors Levy C, Khaled M, Fisher DE.
Title MITF: master regulator of melanocyte development and melanoma oncogene.
Journal Reference Authors Tsao H, Goel V, Wu H, Yang G, Haluska FG.
Title Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma.
Journal Reference Authors Gruss C, Herlyn M.
Title Role of cadherins and matrixins in melanoma.
Journal Reference Authors Thompson JF, Scolyer RA, Kefford RF.
Title Cutaneous melanoma.
Journal Reference Authors Omholt K, Platz A, Kanter L, Ringborg U, Hansson J.
Title NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression.
Journal Clin Cancer Res 9:6483-8 (2003)
Reference Authors Hussein MR.
Title The TP53 tumor suppressor gene and melanoma tumorigenesis: is there a relationship?
Journal Reference Authors Lazar-Molnar E, Hegyesi H, Toth S, Falus A.
Title Autocrine and paracrine regulation by cytokines and growth factors in melanoma.
Journal Related KO pathway LinkDB All DBs
