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| ==Pathophysiology== | | ==Pathophysiology== |
| [[Image:Malignant melanoma.jpg|left|thumb|240px|Nodular melanoma on the leg of an elderly woman.]]
| | ===Molecular Pathogensis=== |
| | | *The development of melanoma first begins with the disruption of nevus growth control. |
| Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental.<ref>[http://www.skincarephysicians.com/skincancernet/who_is_most.html Who is Most at Risk for Melanoma?]</ref> "Intrinsic" factors are generally an individual's family history and inherited [[genotype]], while the most relevant environmental factor is sun exposure.
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| [[Epidemiologic]] studies suggest that exposure to [[ultraviolet]] radiation (UVA<ref name="uva">{{cite journal | author = Wang S, Setlow R, Berwick M, Polsky D, Marghoob A, Kopf A, Bart R | title = Ultraviolet A and melanoma: a review. | journal = J Am Acad Dermatol | volume = 44 | issue = 5 | pages = 837-46 | year = 2001 | id = PMID 11312434}}</ref> and UVB) is one of the major contributors to the development of melanoma. UV radiation causes [[DNA damage|damage]] to the [[DNA]] of cells, typically thymine dimerization, which when unrepaired can create [[mutation]]s in the cell's [[gene]]s. When the cell [[cell division|divides]], these mutations are propagated to new generations of cells. If the mutations occur in [[oncogene]]s or [[tumor suppressor gene]]s, the rate of [[mitosis]] in the mutation-bearing cells can become uncontrolled, leading to the formation of a [[tumor]]. Occasional extreme sun exposure (resulting in "[[sunburn]]") is causally related to melanoma.<ref>{{cite journal | author = Oliveria S, Saraiya M, Geller A, Heneghan M, Jorgensen C | title = Sun exposure and risk of melanoma. | journal = Arch Dis Child | volume = 91 | issue = 2 | pages = 131-8 | year = 2006 | id = PMID 16326797}}</ref> Those with more chronic long term exposure (outdoor workers) may develop protective mechanisms. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure) and is more common in indoor workers than outdoor workers (in a British study<ref>{{cite journal | author = Lee J, Strickland D | title = Malignant melanoma: social status and outdoor work. | journal = Br J Cancer | volume = 41 | issue = 5 | pages = 757-63 | year = 1980 | id = PMID 7426301}}</ref>). Other factors are [[mutation]]s in or total loss of [[tumor suppressor gene]]s. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.
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| ===[[Superficial spreading melanoma]]===
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| ===Genetics=== | | ===Genetics=== |
| Familial melanoma is genetically heterogeneous,<ref>{{cite journal | author = Greene MH. | title = The genetics of hereditary melanoma and nevi. | journal = Cancer | volume = 86 | issue = 11 | pages = 2464-2477 | year = 1998 | id = PMID 10630172}}</ref> and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma.<ref>{{cite journal | author = Halachmi S, Gilchrest BA. | title = Update on genetic events in the pathogenesis of melanoma. | journal = Curr Opin Oncol | volume = 13 | issue = 2 | pages = 129-136 | year = 2001 | id = PMID 11224711}}</ref> The multiple [[Tumor suppressor gene|tumor suppressor]] 1 (CDKN2A/MTS1) gene encodes p16INK4a - a low-molecular weight protein inhibitor of [[cyclin-dependent kinase|cyclin-dependent protein kinases]] (CDKs) - which has been localised to the p21 region of [[Chromosome 9 (human)|human chromosome 9]].<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=1029 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)] from Entrez Gene</ref>
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| <p>Today, melanomas are diagnosed only after they become visible on the skin. In the future, however, physicians will hopefully be able detect melanomas based on a patient’s [[genotype]], not just his or her [[phenotype]]. Recent genetic advances promise to help doctors to identify people with high-risk genotypes and to determine which of a person’s lesions have the greatest chance of becoming cancerous.
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| <p>A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. One class of mutations affects the gene [[CDKN2A]]. An alternative reading frame mutation in this gene leads to the destabilization of [[p53]], a [[transcription factor]] involved in [[apoptosis]] and in fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor of [[CDK4]], a [cyclin-dependent kinase] that promotes cell division. Mutations that cause the skin condition [[Xeroderma Pigmentosum]] (XP) also seriously predispose one to melanoma. Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant.
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| <p>Other mutations confer lower risk but are more prevalent in the population. People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type copies of the gene. [[MC1R]] mutations are very common; in fact, all people with red hair have a mutated copy of the gene.
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| Two-gene models of melanoma risk have already been created, and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype.
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| ==Pathology== | | ==Pathology== |