Key Points
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Melanoma pathogenesis is driven by both genetic and environmental risk factors. Its incidence is influenced by skin pigmentation, sun-exposure history and geographical location.
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About 10% of all melanoma cases are familial. Genetic analysis in familial melanoma patients has identified germline mutations in CDKN2A, which encodes INK4A and ARF, and CDK4. Human and mouse data indicate that inactivation of INK4A–CDK4–RB and ARF–p53 are two near-obligate events in melanoma genesis.
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The red-hair colour (RHC) phenotype has long been associated with an increased risk for melanoma and is linked to specific variants of MC1R. These also increase the penetrance of CDKN2A mutants among germline carriers and are believed to be low-penetrance melanoma-predisposition mutations.
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With the discovery of high-frequency BRAF mutations in melanocytic neoplasms, activation of the RAS–RAF–ERK signalling pathway seems to be yet another near-obligate event in melanoma development.
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Cell-based functional studies, coupled with genetic data in engineered mouse models, have identified MET-HGF activation and loss of the PTEN tumour-suppressor pathway as causal events in melanoma genesis and/or progression.
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Mouse models of melanoma have served as an in vivo genetic platform on which the role and molecular targets of ultraviolet (UV) radiation can be examined. They have provided genetic evidence in support of the epidemiological link between increased melanoma risk and childhood sunburn and have facilitated the identification of components of the RB pathway as specific UV-light targets.
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The search for rational targets for the development of melanoma therapeutics will benefit from the use of inducible onco-transgene models for identification of melanoma-maintenance targets.
Abstract
Therapeutic resistance and proclivity for metastasis are hallmarks of malignant melanoma. Genetic, epidemiological and genomic investigations are uncovering the spectrum of stereotypical mutations that are associated with melanoma and how these mutations relate to risk factors such as ultraviolet exposure. The ability to validate the pathogenetic relevance of these mutations in the mouse, coupled with advances in rational drug design, has generated optimism for the development of effective prevention programmes, diagnostic measures and targeted therapeutics in the near future.
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Acknowledgements
The author would like to thank R. A. DePinho, D. E. Fisher, M. Herlyn, G. Merlino and N. E. Sharpless for critical comments on the manuscript, and to extend her sincere apologies to those colleagues whose studies were not cited in this review because of space constraints. The author is a Charles E. Culpeper Medical Scholar.
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Glossary
- GENOMICS
-
Denotes a systematic, comprehensive, large-scale analysis of biological systems on the genetic level (DNA and RNA) in an automated high-throughput manner. It can be any molecular biological or genetic experiment taken to the whole-genome level.
- EPISTATIC
-
An interaction between non-allelic genes, such that the effect of one gene masks, interferes with or enhances the phenotype of the other gene. Epistasis is not dominance.
- LOSS OF HETEROZYGOSITY
-
(LOH). Occurs when loss of a particular segment of the genome can be shown by the analysis of a polymorphic marker in that region. If an individual is somatically heterozygous for this marker, but homozygous in the tumour, then there has been 'loss of heterozygosity' in that region. Recurrent LOH of a region indicates the presence of a classical tumour-suppressor gene, although recurrent regional loss is also seen for other reasons (for example, because of the presence of fragile sites).
- SV40 T ANTIGEN
-
Simian virus 40 (SV40) is a DNA-transforming virus of the polyomavirus family. SV40 encodes for two 'tumour', or T, antigens — 94 kDa (large T) and 17 kDa (small T). SV40 large T antigen binds to and inactivates the p53 and RB tumour-suppressor proteins.
- PENETRANCE
-
The fraction of individuals of a given genotype that show a particular phenotype, which is usually expressed as a percentage. The penetrance is 'low' when most individuals of a certain genotype do not show the corresponding phenotype. Low penetrance implies that other genes or environmental exposures contribute to the phenotype of interest.
- HAPLOINSUFFICIENCY
-
A phenotypic state that results from loss of one functional allele of any given gene in diploid cells. Sometimes also called allelic insufficiency.
- SKIN PHOTOTYPES
-
Facultative skin colour reflects the genetically-predetermined capacity of the skin to darken in response to ultraviolet radiation, the so-called tanning response. The variation in the tanning response is the basis for division of four skin phototypes, from type I, in which no tanning can occur, to type IV, in which marked tanning occurs.
- MELANIN
-
Melanin is a pigment that is synthesized in melanocytes within specialized cytoplasmic organelles called melanosomes. Melanosomes are transferred to neighbouring keratinocytes within the epidermal melanin unit. The presence of melanized melanosomes within keratinocytes imparts skin and hair colour, which is determined by the number, melanin content and location of the melanosomes.
- PHEOMELANIN AND EUMELANIN
-
These are the two main types of melanin in mammalian skin and hair. Eumelanin is the black-brown pigment. Pheomelanin is the reddish-yellow pigment produced by a shunt in the eumelanin pathway. The relative amounts of pheomelanin and eumelanin determines the skin and hair colour of an individual. Pheomelanin is the predominant pigment found in individuals with red hair and fair complexion, and eumelanin is the predominant pigment found in individuals with black hair and olive complexion.
- PARACRINE
-
A mode of regulation by hormones or growth factors in which their localized release exerts a regional effect on neighbouring cells other than ones that secrete proteins.
- AUTOCRINE
-
A mode of regulation by hormones or growth factors in which release of the protein exerts a positive feedback on the cell(s) producing it.
- COWDEN DISEASE, LHERMITTE–DUCLOS DISEASE AND BANNAYAN–ZONANA SYNDROME
-
Three overlapping autosomal-dominant hamartomatous neoplasm syndromes that are observed in patients with germline PTEN mutations. These patients present with many hamartomas (benign tumours) of the skin and mucosa, gastrointestinal tract, bone, central nervous system, genito-urinary tract, endocrine and exocrine system, with an increased propensity for malignancy (for example, occurring in the breast and thyroid).
- EPIGENETIC
-
Any mode of information transmission from a cell to its descendants without that information being encoded in the nucleotide sequence of the genes.
- ERYTHROGENIC
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A dose of ultraviolet radiation that is sufficient to elicit skin erythema and subsequent peeling, due to direct and indirect damage to specific cellular targets from photochemical reactions and the generation of reactive oxygen species, leading to activation of inflammatory pathways.
- THREE-DIMENSIONAL SKIN RECONSTRUCT SYSTEM
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A system of reconstructing aspects of normal skin in culture. Fibroblasts are embedded in collagen type I to represent the dermis; this is overlaid with progressively differentiated layers of keratinocytes with melanocytes scattered along the basal layer to represent the epidermis. The dermis and epidermis are separated by a basement membrane composed, primarily, of collagen type IV and laminin.
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Chin, L. The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer 3, 559–570 (2003). https://doi.org/10.1038/nrc1145
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DOI: https://doi.org/10.1038/nrc1145
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