Melanoma (WP4685)

Homo sapiens

Melanoma, or malignant melanoma, is a highly aggressive cancer that develops in melanocytes. Many genes have been found to be mutated or amplified in melanoma, with the most commonly mutated genes being BRAF, CDKN2A, NRAS and TP53. MAPK and PI3K/Akt signaling are central to melanoma. This pathway is a summary of information from figures 1 and 2 from [ Kunz and Vera] and supplemented with information from [ KEGG]. CDKN2A is frequently mutated in melanoma and germline mutations are associated with an increased susceptibility of developing skin cancer. The CDKN2A encodes two proteins, p16 (INK4A) and p14ARF, with different functions. p16 binds to CDK4, which prevents phosphorylation of Rb, thereby controlling the G1 to S transition. Without functioning p16, G1 to S transition can proceed. p14ARF is central to cell cycle regulation, inhibiting MDM2, which normally degrades p53, so loss of p14ARF has a similar effect to loss of p53.


Kristina Hanspers , Eric Weitz , Finterly Hu , Egon Willighagen , and Martina Summer-Kutmon


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Homo sapiens


CPTAC Diseases


Disease Ontology


Pathway Ontology

cancer pathway disease pathway


Label Type Compact URI Comment
Vemurafenib Metabolite chebi:63637
Sorafenib Metabolite hmdb:HMDB0014542
PIP3 Metabolite hmdb:HMDB0004249
Regorafenib Metabolite chebi:68647
Dabrafenib Metabolite chebi:75045
Cobimetinib Metabolite wikidata:Q15708292
Binimetinib Metabolite wikidata:Q19903515
KRAS GeneProduct ncbigene:3845
NRAS GeneProduct ncbigene:4893
ETS1 GeneProduct ensembl:ENSG00000134954
GRM3 GeneProduct ensembl:ENSG00000198822
NF1 GeneProduct ensembl:ENSG00000196712
VCL GeneProduct ensembl:ENSG00000035403
RAC1 GeneProduct ensembl:ENSG00000136238
MDM2 GeneProduct ensembl:ENSG00000135679
CDH1 GeneProduct ensembl:ENSG00000039068
KDR GeneProduct ensembl:ENSG00000128052
KIT GeneProduct ensembl:ENSG00000157404
ERBB4 GeneProduct ensembl:ENSG00000178568
PREX2 GeneProduct ensembl:ENSG00000046889
STK19 GeneProduct ensembl:ENSG00000204344
MITF GeneProduct ensembl:ENSG00000187098
PAK1 GeneProduct ensembl:ENSG00000149269
GRB2 GeneProduct ncbigene:2885
SOS2 GeneProduct ncbigene:6655
SOS1 GeneProduct ensembl:ENSG00000115904
HRAS GeneProduct ensembl:ENSG00000174775
ARAF GeneProduct ensembl:ENSG00000078061
BRAF GeneProduct ncbigene:673
RAF1 GeneProduct ncbigene:5894
MAP2K1 GeneProduct ncbigene:5604
MAPK1 GeneProduct ncbigene:5594
MAPK3 GeneProduct ncbigene:5595
MP1 GeneProduct ncbigene:8649
MAP2K2 GeneProduct ncbigene:5605
SHC2 GeneProduct ensembl:ENSG00000129946
ELK1 GeneProduct ncbigene:2002
FOS GeneProduct ncbigene:2353
CREB1 GeneProduct ensembl:ENSG00000118260
PIK3CA GeneProduct ensembl:ENSG00000121879 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18706
PIK3R1 GeneProduct ensembl:ENSG00000145675 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18708
PIK3R2 GeneProduct ensembl:ENSG00000105647 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18709
PIK3CB GeneProduct ensembl:ENSG00000051382 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:74769
PIK3CD GeneProduct ensembl:ENSG00000171608 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18707
PIK3R3 GeneProduct ensembl:ENSG00000117461 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:75669
AKT1 GeneProduct ensembl:ENSG00000142208 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:11651
AKT3 GeneProduct ensembl:ENSG00000117020 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:23797
AKT2 GeneProduct ensembl:ENSG00000105221 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:11652
BAD GeneProduct ensembl:ENSG00000002330 SOS1; son of sevenless homolog 1 (Drosophila)
Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:12015
PTEN GeneProduct ensembl:ENSG00000171862 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:19211
GRIN2A GeneProduct ensembl:ENSG00000183454
CALM1 GeneProduct ensembl:ENSG00000198668
CALM2 GeneProduct ensembl:ENSG00000143933
CALM3 GeneProduct ensembl:ENSG00000160014
CALML3 GeneProduct ensembl:ENSG00000178363
CALML4 GeneProduct ensembl:ENSG00000129007
CALML5 GeneProduct ensembl:ENSG00000178372
CALML6 GeneProduct ensembl:ENSG00000169885
TP53 GeneProduct ensembl:ENSG00000141510
CDKN1A GeneProduct ensembl:ENSG00000124762
BAX GeneProduct ensembl:ENSG00000087088
DDB2 GeneProduct ensembl:ENSG00000134574
POLK GeneProduct ensembl:ENSG00000122008
BAK1 GeneProduct ensembl:ENSG00000030110
GADD45G GeneProduct ensembl:ENSG00000130222
GADD45A GeneProduct ensembl:ENSG00000116717
GADD45B GeneProduct ensembl:ENSG00000099860
CDK6 GeneProduct ensembl:ENSG00000105810 CDK6; cyclin-dependent kinase 6 [EC:2.7.1.-]
RB1 GeneProduct ensembl:ENSG00000139687
CDK4 GeneProduct ensembl:ENSG00000135446 CDK4; cyclin-dependent kinase 4 [EC:2.7.1.-]
CCND1 GeneProduct ensembl:ENSG00000110092 CCND3; cyclin D3
E2F1 GeneProduct ensembl:ENSG00000101412 E2F1; E2F transcription factor 1
E2F2 GeneProduct ensembl:ENSG00000007968 E2F2; E2F transcription factor 2
E2F3 GeneProduct ensembl:ENSG00000112242 E2F3; E2F transcription factor 3
p14 ARF (CDKN2A) GeneProduct ensembl:ENSG00000147889
TP53 GeneProduct ensembl:ENSG00000141510
CDKN1A GeneProduct ensembl:ENSG00000124762
p16 INK4a(CDKN2A) GeneProduct ensembl:ENSG00000147889


  1. KEGG Pathway: hsa05218
  2. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, et al. Nat Genet. 2009 Oct;41(10):1127–32. PubMed Europe PMC Scholia
  3. Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Prickett TD, Wei X, Cardenas-Navia I, Teer JK, Lin JC, Walia V, et al. Nat Genet. 2011 Sep 25;43(11):1119–26. PubMed Europe PMC Scholia
  4. Therapeutic implications of KIT in melanoma. Postow MA, Carvajal RD. Cancer J. 2012;18(2):137–41. PubMed Europe PMC Scholia
  5. Melanoma genome sequencing reveals frequent PREX2 mutations. Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, et al. Nature. 2012 May 9;485(7399):502–6. PubMed Europe PMC Scholia
  6. A landscape of driver mutations in melanoma. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. Cell. 2012 Jul 20;150(2):251–63. PubMed Europe PMC Scholia
  7. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, et al. Nat Genet. 2012 Sep;44(9):1006–14. PubMed Europe PMC Scholia
  8. Genomic Classification of Cutaneous Melanoma. Cancer Genome Atlas Network. Cell. 2015 Jun 18;161(7):1681–96. PubMed Europe PMC Scholia
  9. Modelling of Protein Kinase Signaling Pathways in Melanoma and Other Cancers. Kunz M, Vera J. Cancers (Basel). 2019 Apr 3;11(4):465. PubMed Europe PMC Scholia