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). ... 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). - Genetic Heterogeneity of Susceptibility to Cutaneous Malignant Melanoma Other familial cutaneous malignant melanoma susceptibility loci include CMM2 (155601), caused by variation in the CDKN2A gene (600160) on chromosome 9p21; CMM3 (609048), caused by variation in the CDK4 gene (123829) on chromosome 12q14; CMM4 (608035), mapped to chromosome 1p22; CMM5 (613099), caused by variation in the MC1R gene (155555) on chromosome 16q24; CMM6 (613972), caused by variation in the XRCC3 gene (600675) on chromosome 14q32.3; CMM7 (612263), mapped to chromosome 20q11.22; CMM8 (614456), caused by variation in the MITF gene (156845) on chromosome 3p14.1-p12.3; and CMM9 (615134), caused by variation in the TERT gene (187270) on chromosome 5p15.33. Somatic mutations causing malignant melanoma have also been identified in several genes, including BRAF (164757), STK11 (602216), PTEN (601728), TRRAP (603015), DCC (120470), GRIN2A (138253), ZNF831, and BAP1 (603089). A large percentage of melanomas (40-60%) carry an activating somatic mutation in the BRAF gene, most often V600E (164757.0001) (Davies et al., 2002; Pollock et al., 2003).
Several writers (e.g., Moschella, 1961; Schoch, 1963; Salamon et al., 1963) commented on the usual fair complexion, blue eyes, and multiple ephelides in patients with familial melanoma.
In a questionnaire study, Kopf et al. (1986) found ... Several writers (e.g., Moschella, 1961; Schoch, 1963; Salamon et al., 1963) commented on the usual fair complexion, blue eyes, and multiple ephelides in patients with familial melanoma. In a questionnaire study, Kopf et al. (1986) found that a positive family history for melanoma was correlated with a younger age at first diagnosis in the proband, a smaller diameter of the lesion, lower Clark level, decreased frequency of nonmelanoma skin cancer, and reduced prevalence of noncutaneous cancer. (The Clark index refers to the level of invasion.) A comparison of monozygotic and dizygotic twins for melanoma might be important because of cases of melanoma in non-blood-related members of the same household (Robinson and Manheimer, 1972). Lynch et al. (1978) suggested that a cutaneous marker indicative of susceptibility to malignant melanoma is characterized by large moles, variable in number, reddish brown to pink in color, and with an irregular border. Histologically, they show a bizarre intraepidermal pattern. The authors also described a melanoma family with distinctive freckling and dryness of the skin, suggesting xeroderma pigmentosum (278700) but with normal unscheduled DNA repair and a dominant pedigree pattern. Other malignancies such as colon cancer had an increased frequency in these families. Clark et al. (1978), Greene et al. (1978), and Reimer et al. (1978) pointed out distinctive clinical and histologic features of the moles that are precursors of familial malignant melanomas. They termed these features the 'B-K mole syndrome' after the family names of 2 patients; later, Greene et al. (1980) and Elder et al. (1980) expressed a preference for the designation 'hereditary dysplastic nevus syndrome.' The same lesion underlies some cases of nonfamilial malignant melanoma. Greene et al. (1980) referred to this as 'dysplastic nevus syndrome, sporadic type.' The clinical features include between 10 and 100 moles on the upper trunk and limbs, and variability of mole size (from 5 to 15 mm), outline, and color. Histologically, B-K moles show atypical melanocytic hyperplasia, lymphocytic infiltration, delicate fibroplasia, and new blood vessel formation. Lynch et al. (1980) referred to this as FAMMM (familial atypical mole--malignant melanoma syndrome). Arndt (1984) and Greene et al. (1985) provided photographic illustration of the familial dysplastic nevus syndrome. Lynch et al. (1980) studied 3 kindreds of the FAMMM syndrome. Father-to-son transmission was observed. One patient had 9 separate primary melanomas in 18 years. Expressivity was highly variable. Management is difficult because one cannot be certain which moles require biopsy and then, following histologic study, which require wide excision. The possibility of increased risk of cancer at other sites was raised. Hartley et al. (1987) described several cases of malignant melanoma in close relatives of children with osteosarcoma (259500) and chondrosarcoma (215300). They proposed that in certain families malignant melanoma may be a manifestation of the same gene defect that results in susceptibility to tumors characteristic of the SBLA syndrome (151623). Tucker et al. (2002) described the clinical and histologic features of dysplastic nevi and melanoma over time in families at an increased risk of melanoma with differing germline mutations in CDKN2A (600160) and CDK4 (123829). They evaluated clinically and followed prospectively for up to 25 years a total of 33 families with more than 2 living members with invasive melanoma. A total of 844 family members were examined and photographed. All the families were found to have members with dysplastic nevi and melanoma; 17 had mutations in CDKN2A, 2 had mutations in CDK4, and 14 had no mutations in either gene identified. Most of the dysplastic nevi either remained stable or regressed; few changed in a manner that should have caused concern for melanoma. The melanomas and dysplastic nevi that were found to occur in the study families did not appear to vary by the type of mutation identified in the families. Melanoma-associated retinopathy is a form of paraneoplastic visual disorder that can occur in individuals who have metastatic cutaneous malignant melanoma. Alexander et al. (2004) found that the overall pattern of contrast sensitivity loss shown by patients with melanoma-associated retinopathy was consistent with the dysfunction at the level of the retinal bipolar cells presumed to underlie the disorder.
By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes ... - Somatic Mutations By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. Palavalli et al. (2009) performed mutation analysis of the matrix metalloproteinase (MMP) gene family in human melanoma and identified somatic mutations in 23% of melanomas. Five mutations in one of the most commonly mutated genes, MMP8 (120355), reduced MMP enzyme activity. Expression of wildtype but not mutant MMP8 in human melanoma cells inhibited growth on soft agar in vitro and tumor formation in vivo, suggesting that wildtype MMP8 has the ability to inhibit melanoma progression. Prickett et al. (2009) performed a mutation analysis of the protein tyrosine kinase gene family in cutaneous metastatic melanoma. They identified 30 somatic mutations affecting the kinase domains of 19 protein tyrosine kinases and subsequently evaluated the entire coding regions of the genes encoding these 19 protein tyrosine kinases for somatic mutations in 79 melanoma samples. Prickett et al. (2009) found mutations in ERBB4 (600543) in 19% of individuals with melanoma and found mutations in 2 other kinases (FLT1, 165070 and PTK2B, 601212) in 10% of individuals with melanomas. Prickett et al. (2009) examined 7 missense mutations in ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. Pleasance et al. (2010) sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalog of somatic mutations from an individual cancer. Pleasance et al. (2010) suggested that the catalog provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas an uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. Using exome sequencing followed by screening of targeted genes in melanoma samples, Wei et al. (2011) found 34 distinct somatic mutations in the GRIN2A gene (138253) in 25.2% of 135 melanomas. These findings implicated the glutamate signaling pathway in the pathogenesis of melanoma. Somatic mutations were also found in the TRRAP gene (603015) in 6 (4%) of 167 melanoma samples, and in the DCC gene (120470) in 3 (2%) of 167 melanomas. The most common somatic mutation was V600E in the BRAF gene (164757.0001), which occurred in 65.4% of tumors. Berger et al. (2012) sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per Mb of genome), intermediate in those originating from hair-bearing skin of the trunk (5 to 55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (612139), a PTEN (601728)-interacting protein and negative regulator of PTEN in breast cancer, as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumor formation of immortalized human melanocytes in vivo. Prickett et al. (2011) used exon capture and massively parallel sequencing methods to analyze the mutational status of 734 G protein-coupled receptors in melanoma. This investigation revealed that one family member, GRM3 (601115), was frequently mutated and that 1 of its mutations was recurrent. Biochemical analysis of GRM3 alterations revealed that mutant GRM3 selectively regulated the phosphorylation of MAPK/ERK kinase (MEK; see 176872), leading to increased anchorage-independent growth and migration. Melanoma cells expressing mutant GRM3 had reduced cell growth and cellular migration after short hairpin RNA-mediated knockdown of GRM3 or treatment with a selective MEK inhibitor. Prickett et al. (2011) found that 16.3% of melanomas were affected with GRM3 mutations, making this gene the second most frequently mutated in their study; the most frequently mutated was GPR98 (602851), with a mutation rate of 27.5%. Prickett et al. (2011) found the GRM3 glu870-to-lys mutation in 4 different individuals with melanoma. Nikolaev et al. (2012) performed exome sequencing to detect somatic mutations in protein-coding regions in 7 melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in 2 metastases derived from the same individual. Two melanomas with noncanonical BRAF mutations harbored gain-of-function MAP2K1 (MEK1; 176872) and MAP2K2 (MEK2; 601263) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Stark et al. (2012) sequenced 8 melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, Stark et al. (2012) found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 (602448) or MAP3K9 (600136). Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggested that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W33X variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma. - Genetic Associations Gudbjartsson et al. (2008) found association of a single-nucleotide polymorphism (SNP), dbSNP rs1408799C, which had been associated with eye color (see SHEP11, 612271), with risk of cutaneous malignant melanoma (odds ratio = 1.15, p = 4.3 x 10(-4)).