Molecular Genetics of Melanoma Progression


Cutaneous melanoma is a deadly skin cancer that affects over 200 000 people worldwide each year. Progression from a normal melanocyte to a metastatic melanoma typically occurs in a step‐wise manner, where each stage results from the de‐regulation of certain cell signalling pathways. Cellular senescence is known to play a critical role in melanoma suppression, and genes encoding proteins responsible for cell senescence are commonly mutated in somatic cases of the disease. Germline mutations in these genes can also be found in individuals with familial melanoma. Nonetheless, cutaneous melanoma is not a homogeneous disease, and various sub‐types exist, each displaying variations in certain mutational signatures. Advances in sequencing technologies have allowed researchers to categorise melanoma sub‐types with more precision, as well as to identify novel recurrent gene mutations, which may lead to the development of more personalised therapies in the future.

Key Concepts

  • Mutational clonal evolution of melanoma can be correlated with histopathological lesion types.
  • Oncogenic mutations in MAPK pathway components are the only identified mutations in benign naevi.
  • Benign naevi are in an arrested state called senescence, which must be bypassed for melanoma progression.
  • TERT promoter mutations are common in melanoma and can emerge in dysplastic naevi, although expression of TERT is not sufficient to confer immortality.
  • Invasive melanomas evolve mechanisms to bypass apoptosis, often through excessive PI3K‐AKT signalling.
  • Metastatic melanomas are usually immortal, typically through gain of TERT expression and defects of the p16 pathway.
  • Mutations in familial melanoma genes commonly result in a lengthening of melanocyte proliferative lifespan.

Keywords: melanocyte; cellular senescence; benign naevi; dysplastic naevi; RGP melanoma; VGP melanoma

Figure 1. Model for melanoma progression. In the corresponding genetic model, each successive category typically shows a further genetic or epigenetic change, in pathways mentioned in more detail in the text. Black and red shapes represent naevus and melanoma cells, respectively. Benign naevus cells are relatively uniform in shape and size, whereas dysplastic naevus and melanoma cells are often atypical. Dysplastic naevus and RGP (radial growth phase) melanoma cells are localised to the epidermis (yellow) and papillary dermis (upper blue section), whereas benign naevus and VGP (vertical growth phase) melanoma cells can migrate into the reticular dermis (lower blue section).
Figure 2. Cell signalling pathways commonly altered in melanoma. Proteins coloured red show activating oncogenic mutations in melanoma, while those coloured blue normally act as tumour suppressors and mutations found in melanoma cause defects or deletions. Proteins where mutations have not been found so far in melanoma are uncoloured. See text for more details. ETS transcription factors can only up‐regulate TERT if a promoter mutation occurs, represented as TERT*.


Ackermann J, Frutschi M, Kaloulis K, et al. (2005) Metastasizing melanoma formation caused by expression of activated N‐RasQ61K on an INK4a‐deficient background. Cancer Research 65: 4005–4011.

Alexandrov LB, Nik‐Zainal S, Wedge DC, et al. (2013) Signatures of mutational processes in human cancer. Nature 500: 415–421.

Aoude LG, Pritchard AL, Robles‐Espinoza CD, et al. (2015a) Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. Journal of the National Cancer Institute 107: dju408.

Aoude LG, Wadt KAW, Pritchard AL, et al. (2015b) Genetics of familial melanoma: 20 years after CDKN2A. Pigment Cell & Melanoma Research 28: 148–160.

Arafeh R, Qutob N, Emmanuel R, et al. (2015) Recurrent inactivating RASA2 mutations in melanoma. Nature Genetics 47: 1408–1410.

Bataille V, Kato BS, Falchi M, et al. (2007) Nevus size and number are associated with telomere length and represent potential markers of a decreased senescence in vivo. Cancer Epidemiology, Biomarkers & Prevention 16: 1499–1502.

Bennett DC (2016) Genetics of melanoma progression: the rise and fall of cell senescence. Pigment Cell & Melanoma Research 29: 122–140.

Berger MF, Hodis E, Heffernan TP, et al. (2012) Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485: 502–506.

Bertolotto C, Lesueur F, Giuliano S, et al. (2011) A SUMOylation‐defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480: 94–98.

Bevona C, Goggins W, Quinn T, et al. (2003) Cutaneous melanomas associated with Nevi. Archives of Dermatology 139: 1620–1624.

Bonet C, Luciani F, Ottavi J‐F, et al. (2017) Deciphering the role of oncogenic MITFE318K in senescence delay and melanoma progression. Journal of the National Cancer Institute 109: 415–421.

Chorny JA, Barr RJ, Kyshtoobayeva A, et al. (2003) Ki‐67 and p53 expression in minimal deviation melanomas as compared with other nevomelanocytic lesions. Modern Pathology 16: 525–529.

Christensen C, Bartkova J, Mistrík M, et al. (2014) A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility. Nature Communications 5: 5348.

Clark WH, Elder DE, Guerry D, et al. (1984) A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Human Pathology 15: 1147–1165.

Curtin JA, Fridlyand J, Kageshita T, et al. (2005) Distinct sets of genetic alterations in melanoma. New England Journal of Medicine 353: 2135–2147.

Dankort D, Curley DP, Cartlidge RA, et al. (2009) Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nature Genetics 41: 544–552.

Dhomen N, Reis‐Filho JS, da Rocha DS, et al. (2009) Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15: 294–303.

Fung C, Pupo GM, Scolyer RA, et al. (2013) p16(INK) (4a) deficiency promotes DNA hyper‐replication and genetic instability in melanocytes. Pigment Cell & Melanoma Research 26: 236–246.

Garraway LA, Widlund HR, Rubin MA, et al. (2005) Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436: 117–122.

Garrido MC and Bastian BC (2010) KIT as a therapeutic target in melanoma. Journal of Investigative Dermatology 130: 20–27.

Goldstein AM and Tucker MA (2013) Dysplastic nevi and melanoma. Cancer Epidemiology, Biomarkers & Prevention 22: 528–532.

Govindarajan B, Sligh JE, Vincent BJ, et al. (2007) Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. Journal of Clinical Investigation 117: 719–729.

Gray‐Schopfer VC, Cheong SC, Chong H, et al. (2006) Cellular senescence in naevi and immortalisation in melanoma: a role for p16? British Journal of Cancer 95: 496–505.

Harland M, Petljak M, Robles‐Espinoza CD, et al. (2015) Germline TERT promoter mutations are rare in familial melanoma. Familial Cancer 15: 139–144.

Hodis E, Watson IR, Kryukov GV, et al. (2012) A landscape of driver mutations in melanoma. Cell 150: 251–263.

Hoek KS and Goding CR (2010) Cancer stem cells versus phenotype‐switching in melanoma. Pigment Cell & Melanoma Research 23: 746–759.

Horn S, Figl A, Rachakonda PS, et al. (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339: 959–961.

Huang FW, Hodis E, Xu MJ, et al. (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339: 957–959.

Kohli JS, Tolomio E, Frigerio S, et al. (2017) Common delayed senescence of melanocytes from multiple primary melanoma patients. Journal of Investigative Dermatology 137: 766–768.

Krauthammer M, Kong Y, Ha BH, et al. (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nature Genetics 44: 1006–1014.

Krauthammer M, Kong Y, Bacchiocchi A, et al. (2015) Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun‐exposed melanomas. Nature Genetics 47: 996–1002.

McNeal AS, Liu K, Nakhate V, et al. (2015) CDKN2B loss promotes progression from benign melanocytic nevus to melanoma. Cancer Discovery 5: 1072–1085.

Michaloglou C, Vredeveld LCW, Soengas MS, et al. (2005) BRAFE600‐associated senescence‐like cell cycle arrest of human naevi. Nature 436: 720–724.

Mooi WJ and Krausz T (2007) Cutaneous melanoma. In: Pathology of Melanocytic Disorders, 2nd Ed. edn, pp. 251–389. London: Hodder Arnold.

Nan H, Du M, De Vivo I, et al. (2011) Shorter telomeres associate with a reduced risk of melanoma development. Cancer Research 71: 6758–6763.

Narita M, Nũnez S, Heard E, et al. (2003) Rb‐mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113: 703–716.

Nikolaou V and Stratigos AJ (2014) Emerging trends in the epidemiology of melanoma. British Journal of Dermatology 170: 11–19.

Patton EE, Widlund HR, Kutok JL, et al. (2005) BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Current Biology 15: 249–254.

Pollock PM, Harper UL, Hansen KS, et al. (2003) High frequency of BRAF mutations in nevi. Nature Genetics 33: 19–20.

Prickett TD, Agrawal NS, Wei X, et al. (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nature Genetics 41: 1127–1132.

Prickett TD, Wei X, Cardenas‐Navia I, et al. (2011) Exon capture analysis of G protein‐coupled receptors identifies activating mutations in GRM3 in melanoma. Nature Genetics 43: 1119–1126.

Radu A, Neubauer V, Akagi T, et al. (2003) PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Molecular and Cellular Biology 23: 6139–6149.

Ranade K, Hussussian CJ, Sikorski RS, et al. (1995) Mutations associated with familial melanoma impair p16INK4 function. Nature Genetics 10: 114–116.

Robles‐Espinoza CD, Harland M, Ramsay AJ, et al. (2014) POT1 loss‐of‐function variants predispose to familial melanoma. Nature Genetics 46: 478–481.

Rudolph P, Lappe T, Schubert C, et al. (1995) Diagnostic assessment of two novel proliferation‐specific antigens in benign and malignant melanocytic lesions. American Journal of Pathology 147: 1615–1625.

Salti GI, Manougian T, Farolan M, et al. (2000) Micropthalmia transcription factor: a new prognostic marker in intermediate‐thickness cutaneous malignant melanoma. Cancer Research 60: 5012–5016.

Shain AH, Yeh I, Kovalyshyn I, et al. (2015) The genetic evolution of melanoma from precursor lesions. New England Journal of Medicine 373: 1926–1936.

Shain AH and Bastian BC (2016) From melanocytes to melanomas. Nature Reviews. Cancer 16: 345–358.

Shay JW and Wright WE (2005) Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26: 867–874.

Shi J, Yang XR, Ballew B, et al. (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nature Genetics 46: 482–486.

Soo JK, Mackenzie Ross AD, Kallenberg DM, et al. (2011) Malignancy without immortality? Cellular immortalization as a possible late event in melanoma progression. Pigment Cell & Melanoma Research 24: 490–503.

Stahl JM, Sharma A, Cheung M, et al. (2004) Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Research 64: 7002–7010.

Suram A, Kaplunov J, Patel PL, et al. (2012) Oncogene‐induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO Journal 31: 2839–2851.

Sviderskaya EV, Gray‐Schopfer VC, Hill SP, et al. (2003) p16/cyclin‐dependent kinase inhibitor 2A deficiency in human melanocyte senescence, apoptosis, and immortalization: possible implications for melanoma progression. Journal of the National Cancer Institute 95: 723–732.

The Cancer Genome Atlas Network (2015) Genomic classification of cutaneous melanoma. Cell 161: 1681–1696.

Tsao H, Bevona C, Goggins W, et al. (2003) The transformation rate of moles (melanocytic nevi) into cutaneous melanoma: a population‐based estimate. Archives of Dermatology 139: 282–288.

Vredeveld LCW, Possik PA, Smit MA, et al. (2012) Abrogation of BRAFV600E‐induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes & Development 26: 1055–1069.

Wei X, Walia V, Lin JC, et al. (2011) Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nature Genetics 43: 442–446.

Yeh I, von Deimling A and Bastian BC (2013) Clonal BRAF mutations in melanocytic nevi and initiating role of BRAF in melanocytic neoplasia. Journal of the National Cancer Institute 105: 917–919.

Yokoyama S, Woods SL, Boyle GM, et al. (2011) A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480: 99–103.

Zuo L, Weger J, Yang Q, et al. (1996) Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genetics 12: 97–99.

Further Reading

Bastian BC (2014) The molecular pathology of melanoma: an integrated taxonomy of melanocyte neoplasia. Annual Review of Pathology 9: 239–271.

Muñoz‐Espín D and Serrano M (2014) Cellular senescnece: from physiology to pathology. Nature Reviews. Molecular Cell Biology 15: 482–496.

Tsao H, Chin L, Garraway LA, et al. (2012) Melanoma: from mutations to medicine. Genes & Development 26: 1131–1155.

Zhang T, Dutton‐Regester K, Brown KM, et al. (2016) The genomic landscape of cutaneous melanoma. Pigment Cell & Melanoma Research 29: 266–283.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kohli, Jaskaren S, and Bennett, Dorothy C(Sep 2017) Molecular Genetics of Melanoma Progression. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027340]