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Genetics of Skin Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Melanoma

Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa continued...

In a review of 110 families with multiple cases of pancreatic cancer, 18 showed an association between pancreatic cancer and melanoma.[100] Only 5 of the 18 families with cases of both pancreatic cancer and melanoma had individuals with multiple dysplastic nevi. These 18 families were assessed for mutations in CDKN2A; mutations were identified in only 2 of the 18 families, neither of which had a dysplastic nevi phenotype.

Melanoma-astrocytoma syndrome

The melanoma-astrocytoma syndrome is another phenotype caused by mutations in CDKN2A. The possible existence of this disorder was first described in 1993.[101] A study of 904 individuals with melanoma and their families found 15 families with 17 members who had both melanoma and multiple types of tumors of the nervous system.[102] Another study found a family with multiple melanoma and neural cell tumors that appeared to be caused by loss of p14ARF function or to disruption of expression of p16.[103]

Telomerase reverse transcriptase(TERT)

Linkage of melanoma to a region of chromosome 5p was observed in a single large kindred with multiple melanomas and other cancers.[104] Sequencing demonstrated a mutation in the promoter region of a subunit of TERT, which in construct assays demonstrated increased promoter activity. This mutation cosegregated with melanoma and other cancers, including ovarian, renal, bladder, and bronchial, with multiple cancers observed in single individuals. At least one affected family member was observed to have numerous nevi. Somatic mutations in the same region were observed in 125 of 168 sporadic melanomas in the same report.[104] A separate study reported mutations that also increased promoter activity in the same TERT promoter region in 50 of 70 sporadic melanomas. [105] Similar mutations were seen in 16% of a diverse set of established cancer cell lines, suggesting this might be a common activation mutation in multiple cancer types. The frequency of this mutation in melanoma families has not yet been investigated.

CDK4 and CDK6

Cyclin-dependent kinases have important roles in progression of cells from G1 to S phase. CDK4 and CDK6 partner with the cyclin–D associated kinases to accelerate the function of the cell cycle. Phosphorylation of the retinoblastoma (Rb) protein in G1 by cyclin-dependent kinases releases transcription factors, inducing gene expression and metabolic changes that precede DNA replication, thus allowing the cell to progress through the cell cycle. These genes are of conceptual significance because they are in the same signaling pathway as CDKN2A.

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