Melanoma, Cutaneous Malignant, Susceptibility To, 9

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

CDKN2A, MC1R, MGMT, CDK4, CDKN2B, ACD, TERF2IP, POT1, BAP1, TERT, MITF, H3P10, CMM, IFNA13, IFNA2, IFNA1, HRAS, IFN1@, IFNA17, XPA, CHRM1, HPRT1, XRS, TP53, TYR, PTH, NPPA, MYCL, CDK2, BRCA2

Drugs

Aldesleukin ( PROLEUKIN ), HLA-A2 restricted CD8 T-cell line expressing MART-1 T-cell receptor, Imexon

Aldesleukin ( PROLEUKIN ), HLA-A2 restricted CD8 T-cell line expressing MART-1 T-cell receptor, Imexon, Melphalan ( EVOMELA, ALKERAN ), Oblimersen

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A number sign (#) is used with this entry because of evidence that susceptibility to cutaneous malignant melanoma-9 (CMM9) is conferred by variation in the TERT gene (187270) on chromosome 5p15.

Description

Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010).

For a discussion of genetic heterogeneity of malignant melanoma, see 155600.

Clinical Features

Horn et al. (2013) reported a 4-generation family with 14 melanoma patients who were not carriers of germline mutations in the melanoma susceptibility genes CDKN2A (600160) or CDK4 (123829). Two family members had additional forms of cancer. One individual, who developed melanoma at the age of 20, later developed ovarian cancer, renal cell carcinoma, bladder cancer, mammary carcinoma, and finally bronchial carcinoma, leading to her death at age 50. The other individual presented with ovarian cancer at age 27 and melanoma at age 30.

Mapping

Horn et al. (2013) performed multipoint linkage analysis in a 4-generation family with 14 melanoma patients, which showed a possible 2.2-Mb linkage region on chromosome 5p with maximal lod scores of 2.35 at rs1379917 and 2.45 at rs1968011.

Molecular Genetics

Using target-enriched high-throughput sequencing of a region on chromosome 5p identified by linkage analysis in a family segregating cutaneous malignant melanoma, Horn et al. (2013) identified a T-to-G transversion at the -57 position from the ATG translation start site of TERT (187270.0023) in all 4 affected family members sequenced and in 1 unaffected family member. This mutation was not found among 140 sporadic melanoma cases, 165 healthy controls, index cases from 34 Spanish melanoma families, or in the dbSNP or 1000 Genomes Project databases.

Horn et al. (2013) identified recurrent ultraviolet signature mutations in the TERT core promoter in 125 of 168 cell lines (74%), in 45 of 53 corresponding metastatic tumor tissues (85%) and in 25 of 77 (33%) primary melanomas. Two frequent mutations, G-to-A (C-to-T on the opposite strand) transitions at positions -124 and -146, were mutually exclusive and occurred in 27% and 38% of cell lines, respectively. These mutations generate binding motifs for ETS/TCF (ternary complex factor) transcription factors. Among 77 paraffin-embedded primary melanoma tumors, the -124G-A mutation was found in 7 (9%) and the -146G-A mutation in 5 (7%).

Huang et al. (2013) independently found the -124G-A and -146G-A TERT promoter mutations, which they called C228T and C250T, respectively, in 50 (71%) of 70 of melanomas examined.