Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Skin: Melanoma

Written2007-05Marco Castori, Paola Grammatico
Laboratory of Molecular, Cell Biology, Isituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta, 104, 00168 Rome, Italy (MC); Medical Genetics, Experimental Medicine, Pathology Department, University La Sapienza, S. Camillo-Forlanini Hospital, Gianicolense n. 87, 00152 Rome, Italy (PG)

(Note : for Links provided by Atlas : click)


ICD-Topo C440-C449 SKIN
ICD-Morpho 8720/3 Malignant melanoma, NOS
Atlas_Id 5416
Phylum Lung, Heart, Skin, Other::Melanoma
WHO/OMS Classification Lung, Heart, Skin, Other
Other namesCutaneous melanoma
Melanoma skin cancer


Note Skin melanoma is a relatively common human cancer with an increasing incidence trend and originates from skin melanocytes, which are neural crest derived cells. Melanoma arises in more than 95% of cases in the skin, although other sites of primary extracutaneous melanoma include uvea , oral and genital mucosae, gastrointestinal and genitourinary tracts, leptomeninges and lymph nodes

Clinics and Pathology

Embryonic origin Neural crest cells (this embryonic origin is valid for all forms of melanoma, except for uveal melanoma, which derives from neuroectodermal cells .
Etiology A wide spectrum of risk factors for skin melanoma has been unravelled in the last decades. They are classically distinguished in host and environmental factors. The strongest host conditions are positive family history for melanoma (especially in first-degree relatives and in a number of 3 or more), multiple benign (often more than 100) or atypical nevi (the so-called dysplastic nevus syndrome), and a previous melanoma. The first two risk factors may coexist in the same pedigree, thus delineating the Familial Atypical Mole - Multiple Melanoma syndrome (or FAMMM syndrome). Among these families, 30-40% of them display mutations in the CDKN2A gene, while a few kindreds are mutated in CDK4. Other host factors that may increase the risk of developing melanoma are previous non-melanoma skin cancer and immunosuppression (such as, transplant recipients or patients with AIDS).
However, solar UVR exposure remains the leading cause for developing skin melanoma. In fact, skin melanoma is strikingly more common in patients with type I skin, freckling, blue eyes and red hair. This evidence demonstrates that host and environmental risk factors cooperate in determining the onset and evolution of skin melanoma (this interaction has been recently demonstrated at the molecular level. In fact, ultraviolet exposure stimulates tanning in part inducing the action of the alpha-melanocyte-stimulating hormone (POMC) on the melanocortin receptor 1 - MC1R. Light-skinned and readheaded people carry specific MC1R polymorphisms that reduce its activity). Accumulated evidences support that intermittent sun exposure is a major determinant for melanoma in contrast with cumulative sun exposure, as well as a history of blistering sunburn, especially in young age (i.e. three or more episodes before 20 years). The risk related to non-solar UVR exposure is still debated.
Epidemiology Melanoma is the fifth most common cancer in men and the sixth in women (note that this ranking may slightly vary among distinct populations and different epidemiological studies). It accounts for nearly 4% of all dermatologic cancers, but represents the major cause of death for skin cancer. The overall incidence of melanoma ranges from 10 to 42 new cases for 100.000 per year. This apparent wide variability may essentially relay on the ethnic background of the population studied. The incidence of melanoma is rising by 3-8% per year in most people of European origin. Melanoma affects young and middle aged people, with a median age at diagnosis of 57 years. The cancer incidence increase progressively after the age of 15 years until the age of 50 and then slows, especially in females, who are slightly less affected than men (males are approximately 1.5 times more likely to develop melanoma than females). Nearly half of the patients have an age comprised from 35 and 65 years at diagnosis.
Clinics Melanoma should be considered for every suspicious pigmented skin lesions. There are specific characteristics to be taken into account for identifying suspicious lesions which request further investigations. The acronym ABCDE summarizes five cardinal features, including:
  • (i) Asymmetry;
  • (ii) Border irregularity;
  • (iii) Color variation;
  • (iv) Diameter above 6 mm; and
  • (v) Evolving, which encompasses any significant change in size, shape, surface, shades of color or symptoms (such as, itching).
    Clinical suspicion must be supported by assistive optical devices, such as dermatoscopes, epiluminescent microscopes and/or other portable scanning units using visible, infrared and UV sources. However, a firm diagnosis is reached only by excision and histologic examination.
  • Pathology Pathologic staging of skin melanoma is crucial for prognosis definition and management planning. The Clark's model identifies 5 steps in the progression from benign nevus and metastatic melanoma:
  • step 1: benign nevus;
  • step 2: dysplastic nevus;
  • step 3: radial-growth phase melanoma;
  • step 4: vertical-growth phase melanoma;
  • step 5: metastatic melanoma.
    This model also denotes qualitative anatomic levels of invasion:
  • In level I melanoma, all tumor cells are above the basement membrane (malignant melanoma in situ).
  • Level II melanoma invades into the papillary dermis.
  • Level III melanoma fills and expands the papillary dermis.
  • Level IV melanoma invades the reticular dermis, while
  • level V melanoma reaches the subcutaneous adipose tissue.
    Actually, for the T staging of melanoma the primary determinant is the Breslow's technique, that provides a quantitative measurement of the depth of invasion by measuring the tumor thickness with an ocular micrometer (in millimeters).
  • T1 melanomas are = 1.0 mm in thickness,
  • T2 between 1.01 and 2.00 mm,
  • T3 between 2.01 and 4.00 mm, and
  • T4 above 4.0 mm.
    To date, the Clark's level system is the primary prognostic method only for T1 melanomas.
    The melanoma clinical staging include four stages.
  • Stage I melanomas are those with thickness that are 1 mm or less with no evidence of metastases.
  • Stage II melanoma is diagnosed in patients with thicker cancers without evidence of metastases.
  • Stage III melanomas are those with regional lymph nodes and/or an in-transit or satellite metastasis.
  • Stage IV cancer is diagnosed when the melanoma spreads to distant sites.
    Specific determinants define the N and M axes for stage III and IV melanomas.
    There are unusual variants of melanoma (for which the standard prognostic factors should be taken into account), that must be differentiated form epithelial or mesenchymal neoplasms.
    These variants include: desmoplastic melanoma, mucosal melanoma, malignant blue nevus, nevoid melanoma, minimal deviation melanoma, small cell melanoma, spitzoid melanoma, dermal melanoma, amelanotic melanoma, myxoid melanoma, signet ring melanoma, balloon cell melanoma, rhabdoid melanoma, pigment-synthesizing animal melanoma, osteoid melanoma, chondroid and cartilagineous melanoma, and basomelanocytic tumor.
  • Treatment After histologic diagnosis of melanoma, the first step is the extent of excision. The radius of this excision depends on the tumor thickness (Breslow's technique).
    Sentinel lymph node biopsy is requested in melanomas of Stage I.
    In melanomas with thickness above 2 mm, elective lymph node dissection is also recommended. Surgical excision could be considered also for local recurrences, in-transit metastases, regional metastases and in patients with metastatic disease.
    In stage III patients, the eradication of clinical undetectable micrometastases at the time of diagnosis may be obtained using adjuvant therapy, including interferon-alpha and ganulocyte-macrophage colony-stimulating factor.
    In stage IV cancers the systemic therapy is based on decarbazide, interleukin-2, in isolation or in combination with other chemotherapeutic agents. Novel therapeutic regimens include cancer vaccines, angiogenesis inhibitors and novel cytotoxic agents.
    Evolution Usually, skin melanomas show two distinct phases of local invasion:
  • (i) the radial-growth phase, during which tumor cells acquire the ability to proliferate intraepidermally;
  • (ii) the vertical-growth phase, which is characterized by tumor invasion of the dermis in form of an expansile nodule.
    Local invasive melanomas may reach distant skin areas and subcutis. The invasion of lymph vessels leads to lymph node metastases.
    Finally, metastatic melanomas may metastasize to lungs, liver, central nervous system and other organs.
  • Prognosis The prognosis (i.e. % of 10-year survival rate) is directly related to the Pathologic stage. This range from 100% for melanoma in situ to less than 6% for patients with a stage IV melanoma with distant metastases.


    Numerical and structural changes visible by standard cytogenetics are common in sporadic melanoma, which is frequently aneuploid with a modal chromosomal set usually ranging from 24 to more than 100.
    The most common abnormality involves chromosome 1 with deletions and translocations usually including the region 1p12-22. A recurrent t(1;19) translocation has been also described in a subset of sporadic melanomas.
    Deletions or translocations involving the long arm of one or both chromosome 6, commonly affecting the 6q16-23 region, are observed in nearly 80% of skin melanomas. The 6 chromosome short arm is generally retained in form of an isochromosome (i6p). The gain of the short arm of chromosome 6 may have a role in cancer progression, especially for metastastic evolution (in fact, the NEDD9 gene, whose overexpression in associated to metastatic melanomas, maps in 6p25-p24).
    An equally common alteration is the gain of copies of chromosome 7. This finding is usually associated with late stages of skin melanoma.
    A second set of chromosome abnormalities includes alterations of chromosome 2, 3, 9, 10 and 11. Among them, a recurrent site of alterations (predominantly deletions) in both premalignant nevi and metastatic melanomas is the short arm of chromosome 9, particularly the region 9q21. Loss of chromosome 10, especially involving the region 10q24-26, seems to be implicated in both the early and late stages of melanocytic neoplasia. In late stage melanomas, chromosome 10 loss often accompanies chromosome 7 gain. At the standard cytogenetic level, the rate of involvement of other chromosomes (i.e. 2, 3 and 11) is less consistent.
    Cytogenetics Molecular A large number of studies have searched for loss of heterozygosity (LOH), homozygous deletions (HD) and amplifications in cutaneous melanomas, events that are difficult or impossible to identify at the standard cytogenetic level.
    Over the years, the improvement of laboratory techniques has collected a wide range of different approaches, including fluorescent in situ hybridization, standard microsatellite analysis on specific genomic regions and conventional chromosome-based comparative genomic hybridization array. Actually, the most sensitive technique is the high-density whole-genome single nucleotide polymorphism array, which is able to detect variations in number of copies of genomic DNA within an interval of only 9 kb. Therefore, the results of this type of analysis is by far the most sensitive among all available approaches.
    Overall, whole chromosome arm LOH is most common on 9p, 9q, 10p and 10q, occurring in 40-50% of the cases. Considering focal (i.e. small portion of chromosome arms) LOH, these chromosome regions are involved in 49-72% of the cases. Over 40% of analyzed melanomas show LOH on 6q, 11q and 17p, while 33% on 5q. A broad spectrum of HD has been also registered and involves regions containing both well known melanoma progression associated genes (such as, CDKN2A and PTEN - for more details, see Genes Involved and Proteins section), and other genes, whose role in cancer evolution awaits further elucidations. In more that one fourth (25%) of melanomas there are chromosome gains involving 7p, 20q and 22q. Amplifications of single genes may be also detected by this technique, but these data will be discussed in the next section. The 8q region, in which maps the C-MYC gene, is amplified in nearly 14% of the cases.

    Genes involved and Proteins

    Note Several genes have been discovered as involved in the progression of cutaneous melanoma. Two major groups of genes have been identified: tumor suppressor genes and proto-oncogenes. In order to describe melanoma progression implicated genes, the present section follows this classification. In addition to those here described, other genes, such as NF1, NF2, TTC4, NME2, CDKN1A, and RAB8A, have been sporadically studied in melanomas, but the present data are still very limited and not completely conclusive.
    Gene NameB2M (beta-2-microglobulin)
    Location 15q21.1
    Note Escape by melanoma cells from T cell recognition through a complete lack of HLA class I antigen can be ascribed to beta-2-microglobulin (encoded by the B2M gene) aberrations. The combination of LOH and somatic mutation leading to a biallelic inactivation of B2M is not uncommon in melanoma cells.

    Gene NameCDK11B (cyclin dependent kinase 11B)
    Location 1p36.33
    Note This genes maps in a chromosome region (i.e. 1q36) frequently deleted in melanoma. However, mutations in this gene are rare and the role of this gene in tumor progression is probably very limited.

    Gene NameCDKN2A (cyclin dependent kinase 2a / p16)
    Location 9p21.3
    Note The CDKN2A locus shows LOH in nearly 50% of melanomas, while point mutations of this gene are extremely rare, probably because other mechanisms are involved in its inactivation (such as promoter methylation or homozygous deletion).

    Gene NameCDKN2B (cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4))
    Location 9p21.3
    Note CDKN2B maps nearly to CDKN2A and shares with this gene an high sequence homology. Although CDKN2B maps in a commonly deleted region in melanoma, the frequency of point mutations is relatively low and the actual knowledge about the role of this gene in melanoma progression is limited.

    Gene NameMEN1 (multiple endocrine neoplasia I)
    Location 11q13.1
    Note Mutations in menin, the gene responsible for the multiple endocrine neoplasia type I (MEN1), results mutated in nearly 1% of the analyzed melanomas.

    Gene NamePTEN (Phosphatase and Tensin homolog deleted on chromosome Ten)
    Location 10q23.31
    Note The chromosome region in which this gene maps is deleted in about 30-50% of melanomas, while somatic PTEN mutations have been identified in approximately 3% primary melanomas and 8% metastatic melanomas.

    Gene NameRB1 (retinoblastoma)
    Location 13q14.2
    Note Although the implications of CDKN2A and CDK4 (see below) is crucial in melanoma progression, the actual rate of mutations or rearrangement involving this gene, which is implicated in the same pathway, is extremely rare and confined to sporadic cases.

    Gene NameTFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha))
    Location 6p24.3
    Note Loss of AP2-alpha (the protein encoded by TFAP2A) expression is a crucial event in the melanoma development. However, the frequency of TFAP2A somatic mutations in melanomas is extremely low, thus suggesting that the AP2-alpha underexpression is very probably caused by the caspasis activity.

    Gene NameTP53 (Tumour protein p53 (Li-Fraumeni syndrome))
    Location 17p13.1
    Note TP53 mutations in melanomas are rare, occurring in 0-24% (mean 7%) of the analyzed tumors. However, UVR is very likely the cause of these mutations, as well as in other non-melanocytic skin tumors.

    Gene NameWnt signalling pathway tumor suppressor genes.
    Location Variable (see text).
    Note The involvement of this pathway in melanoma progression is clearly demonstrated by the overexpression of beta-catenin in nearly 30% of the cases. Several genes coding for proteins implicated in the modulation of this pathway has been studied for somatic mutations in relation with melanoma. Among them, the most frequently somatically mutated gene is LKB1 (i.e. the gene responsible of Peutz-Jeghers syndrome; location: 19p13.3) with an overall mutation frequency in melanoma of 4%. Other related genes, namely PPP2R1A (location: 19q13.4), APC (whose germline mutations are associated with the familial adenomatous polyposis; location: 5q21-q22) and ICAT (location: 1p36.22), are only rarely mutated in melanomas.

    Note Proto-oncogenes:

    Gene NameCDK4 (cyclin-dependent kinase 4)
    Location 12q14.1
    Note The primary role of the protein encoded by CDK4 is to inactivate pRB. Mutations that constitutively activate the kinase, in particular those involving the K22 and R24 aminoacid residues, have been identified in a variable proportion, ranging from 1/60 to 5/48, of the cases.

    Gene NameCTNNB1 (Catenin, beta-1)
    Location 3p22.1
    Note This gene encodes for beta-catenin. As this protein is overexpressed in about one third of the cases, several studies investigated the presence of somatic mutations in this gene. The overall frequency of CTNNB1 somatic mutations in melanoma is 2-5%.

    Gene NameMAPK signalling pathway proto-oncogenes.
    Location Variable (see text).
    Note This pathway may be simplified as follows. The growth factor receptor interaction with its ligand induces the activation of RAS. Its activation stimulates phosphorylation of RAF proteins (including BRAF), that in turn activate MEK1 and MEK2. The final step of this cascade is the transcription factors activation by ERK 1 and ERK 2, which are phosphorilated by MEK proteins.
    BRAF (location: 7q34) mutations have been identified in more than 60% of melanomas and approximately 80% of these mutations occur at a single site, leading to the substitution of valine at position 600 with glutamic acid (V600E). This change mimics phosphorylation within the activation segment and results in constitutive activation of BRAF. The frequency of BRAF mutations in melanocytic nevi is similar to that in melanomas, suggesting that BRAF function perturbation is an early event in melanoma development and is not sufficient to determine the neoplastic switch. The rate of BRAF mutation varies among melanoma subtypes and is highest in nodular melanoma and superficial spreading melanoma. BRAF mutations appear to be less common in sun-exposed areas. BRAF mutations are mutually exclusive to those occurring in the NRAS gene (1p13.2). The most common sites of mutation in this gene are codon 12, 13, 18 and 61.
    In contrast to BRAF mutations, NRAS alterations are more common in sun-exposed areas. This fact suggests that NRAS mutations may arise as a result of UVR-induced mutagenesis.
    HRAS (location: 11p15.5) mutations are less commonly observed and occurs in no more than 1.5-3% of melanomas.
    Activating changes in KRAS2 (location: 12p12.1) have been observed in rare cases and often associate with mutations in other RAS genes (i.e. NRAS and HRAS). Therefore, KRAS2 in a not powerful oncogene in melanoma progression.

    To be noted

    At the moment, only a fragmented picture has emerged about the molecular and cellular events that mirror the progression from benign nevus to melanoma. Probably, BRAF mutation represent the starting event leading to the formation of a benign nevus. The transformation in dysplastic nevus is characterized by loss of expression of CDKN2A and/or PTEN. Increased CD1 marks the radial-growth phase, while the vertical-growth phase requests a wider spectrum of molecular events, such as loss of E-cadherin, expression of N-cadherin, alphaV-beta3 integrin and MMP-2 as well as the reduction of TRPM1. Total absence of TRPM1 and overexpression of NEDD9 characterize the metastatic phase.


    Cancer in Australia 2000.
    Australian Institute of Health and Welfare AIHW, Australasian Association of Cancer Registries AACR 2003
    Canberra. : page AI.
    LKB1 somatic mutations in sporadic tumors.
    Avizienyte E, Loukola A, Roth S, Hemminki A, Tarkkanen M, Salovaara R, Arola J, Btzow R, Husgafvel-Pursiainen K, Kokkola A, Jrvinen H, Aaltonen LA
    The American journal of pathology. 1999 ; 154 (3) : 677-681.
    PMID 10079245
    Ras mutations in human melanoma: a marker of malignant progression.
    Ball NJ, Yohn JJ, Morelli JG, Norris DA, Golitz LE, Hoeffler JP
    The Journal of investigative dermatology. 1994 ; 102 (3) : 285-290.
    PMID 8120410
    The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis.
    Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J, Bartek J
    Cancer research. 1996 ; 56 (23) : 5475-5483.
    PMID 8968104
    Classifying melanocytic tumors based on DNA copy number changes.
    Bastian BC, Olshen AB, LeBoit PE, Pinkel D
    The American journal of pathology. 2003 ; 163 (5) : 1765-1770.
    PMID 14578177
    Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma.
    Breslow A
    Annals of surgery. 1970 ; 172 (5) : 902-908.
    PMID 5477666
    The histogenesis and biologic behavior of primary human malignant melanomas of the skin.
    Clark WH Jr, From L, Bernardino EA, Mihm MC
    Cancer research. 1969 ; 29 (3) : 705-727.
    PMID 5773814
    Cytogenetic analysis of melanocytes from premalignant nevi and melanomas.
    Cowan JM, Halaban R, Francke U
    Journal of the National Cancer Institute. 1988 ; 80 (14) : 1159-1164.
    PMID 3166071
    Mutations of the BRAF gene in human cancer.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA
    Nature. 2002 ; 417 (6892) : 949-954.
    PMID 12068308
    Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma.
    Demunter A, Stas M, Degreef H, De Wolf-Peeters C, van den Oord JJ
    The Journal of investigative dermatology. 2001 ; 117 (6) : 1483-1489.
    PMID 11886512
    Loss of alleles from the distal short arm of chromosome 1 occurs late in melanoma tumor progression.
    Dracopoli NC, Harnett P, Bale SJ, Stanger BZ, Tucker MA, Housman DE, Kefford RF
    Proceedings of the National Academy of Sciences of the United States of America. 1989 ; 86 (12) : 4614-4618.
    PMID 2734311
    Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma.
    Flores JF, Walker GJ, Glendening JM, Haluska FG, Castresana JS, Rubio MP, Pastorfide GC, Boyer LA, Kao WH, Bulyk ML, Barnhill RL, Hayward NK, Housman DE, Fountain JW
    Cancer research. 1996 ; 56 (21) : 5023-5032.
    PMID 8895759
    Genetics of melanoma.
    Fountain JW, Bale SJ, Housman DE, Dracopoli NC
    Cancer surveys. 1990 ; 9 (4) : 645-671.
    PMID 2101727
    Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor.
    Frndberg PA, Doufexis M, Kapas S, Chhjlani V
    Biochemical and biophysical research communications. 1998 ; 245 (2) : 490-492.
    PMID 9571181
    Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.
    Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR
    Nature. 2005 ; 436 (7047) : 117-122.
    PMID 16001072
    Homozygous loss of the p15INK4B gene (and not the p16INK4 gene) during tumor progression in a sporadic melanoma patient.
    Glendening JM, Flores JF, Walker GJ, Stone S, Albino AP, Fountain JW
    Cancer research. 1995 ; 55 (23) : 5531-5535.
    PMID 7585628
    Localization of multiple melanoma tumor-suppressor genes on chromosome 11 by use of homozygosity mapping-of-deletions analysis.
    Goldberg EK, Glendening JM, Karanjawala Z, Sridhar A, Walker GJ, Hayward NK, Rice AJ, Kurera D, Tebha Y, Fountain JW
    American journal of human genetics. 2000 ; 67 (2) : 417-431.
    PMID 10877980
    Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma.
    Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J
    Oncogene. 1999 ; 18 (9) : 1777-1780.
    PMID 10208439
    Allelotypes of primary cutaneous melanoma and benign melanocytic nevi.
    Healy E, Belgaid CE, Takata M, Vahlquist A, Rehman I, Rigby H, Rees JL
    Cancer research. 1996 ; 56 (3) : 589-593.
    PMID 8564976
    Loss of heterozygosity in sporadic primary cutaneous melanoma.
    Healy E, Rehman I, Angus B, Rees JL
    Genes, chromosomes & cancer. 1995 ; 12 (2) : 152-156.
    PMID 7535089
    Multiple karyotypic abnormalities, including structural rearrangements of 11p, in cell lines from malignant melanomas.
    Heim S, Mandahl N, Arheden K, Giovanella BC, Yim SO, Stehlin JS Jr, Mitelman F
    Cancer genetics and cytogenetics. 1988 ; 35 (1) : 5-20.
    PMID 3180009
    A defined region of loss of heterozygosity at 11q23 in cutaneous malignant melanoma.
    Herbst RA, Larson A, Weiss J, Cavenee WK, Hampton GM, Arden KC
    Cancer research. 1995 ; 55 (12) : 2494-2496.
    PMID 7780954
    Beta2-microglobulin gene mutations in human melanoma cells: molecular characterization and implications for immune surveillance.
    Hicklin DJ, Dellaratta DV, Kishore R, Liang B, Kageshita T, Ferrone S
    Melanoma research. 1997 ; 7 Suppl 2 : S67-S74.
    PMID 9578419
    Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis.
    Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M
    The EMBO journal. 1998 ; 17 (15) : 4358-4369.
    PMID 9687504
    Cancer statistics, 2004.
    Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, American Cancer Society, Thun MJ
    CA: a cancer journal for clinicians. 2004 ; 54 (1) : 8-29.
    PMID 14974761
    Microsatellite instability analysis in tumors with different mechanisms for total loss of HLA expression.
    Jimenez P, Cantn J, Concha A, Cabrera T, Fernndez M, Real LM, Garca A, Serrano A, Garrido F, Ruiz-Cabello F
    Cancer immunology, immunotherapy : CII. 2000 ; 48 (12) : 684-690.
    PMID 10752476
    N-ras mutations are common in melanomas from sun-exposed skin of humans but rare in mucosal membranes or unexposed skin.
    Jiveskog S, Ragnarsson-Olding B, Platz A, Ringborg U
    The Journal of investigative dermatology. 1998 ; 111 (5) : 757-761.
    PMID 9804334
    Is there a role for genetic testing in patients with melanoma?
    Kefford RF, Mann GJ
    Current opinion in oncology. 2003 ; 15 (2) : 157-161.
    PMID 12601281
    Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color.
    Kennedy C, ter Huurne J, Berkhout M, Gruis N, Bastiaens M, Bergman W, Willemze R, Bavinck JN
    The Journal of investigative dermatology. 2001 ; 117 (2) : 294-300.
    PMID 11511307
    Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene.
    Kim M, Gans JD, Nogueira C, Wang A, Paik JH, Feng B, Brennan C, Hahn WC, Cordon-Cardo C, Wagner SN, Flotte TJ, Duncan LM, Granter SR, Chin L
    Cell. 2006 ; 125 (7) : 1269-1281.
    PMID 16814714
    Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases.
    Kraehn GM, Utikal J, Udart M, Greulich KM, Bezold G, Kaskel P, Leiter U, Peter RU
    British journal of cancer. 2001 ; 84 (1) : 72-79.
    PMID 11139316
    A single nucleotide polymorphism in the 3'untranslated region of the CDKN2A gene is common in sporadic primary melanomas but mutations in the CDKN2B, CDKN2C, CDK4 and p53 genes are rare.
    Kumar R, Smeds J, Berggren P, Straume O, Rozell BL, Akslen LA, Hemminki K
    International journal of cancer. Journal international du cancer. 2001 ; 95 (6) : 388-393.
    PMID 11668523
    Gross rearrangements and deletions of the retinoblastoma gene are rare in malignant melanoma.
    Lewis DC, Warren N, Shukla VK, Grimshaw D, Laidler P, Padua RA
    Acta dermato-venereologica. 1993 ; 73 (3) : page 236.
    PMID 8105633
    Chromosome changes in metastatic human melanoma.
    Limon J, Dal Cin P, Sait SN, Karakousis C, Sandberg AA
    Cancer genetics and cytogenetics. 1988 ; 30 (2) : 201-211.
    PMID 3422577
    Loss of heterozygosity analysis of cutaneous melanoma and benign melanocytic nevi: laser capture microdissection demonstrates clonal genetic changes in acquired nevocellular nevi.
    Maitra A, Gazdar AF, Moore TO, Moore AY
    Human pathology. 2002 ; 33 (2) : 191-197.
    PMID 11957144
    Determinants of BRAF mutations in primary melanomas.
    Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, Ono T, Albertson DG, Pinkel D, Bastian BC
    Journal of the National Cancer Institute. 2003 ; 95 (24) : 1878-1890.
    PMID 14679157
    Malignant melanoma in the 21st century, part 2: staging, prognosis, and treatment.
    Markovic SN, Erickson LA, Rao RD, Weenig RH, Pockaj BA, Bardia A, Vachon CM, Schild SE, McWilliams RR, Hand JL, Laman SD, Kottschade LA, Maples WJ, Pittelkow MR, Pulido JS, Cameron JD, Melanoma Study Group of Mayo Clinic Cancer Center, Creagan ET
    Mayo Clinic proceedings. Mayo Clinic. 2007 ; 82 (4) : 490-513.
    PMID 17418079
    Mutations of p16 and p15 tumor suppressor genes and replication errors contribute independently to the pathogenesis of sporadic malignant melanoma.
    Matsumura Y, Nishigori C, Yagi T, Imamura S, Takebe H
    Archives of dermatological research. 1998 ; 290 (4) : 175-180.
    PMID 9617435
    Miller AJ, Mihm MC Jr
    The New England journal of medicine. 2006 ; 355 (1) : 51-65.
    PMID 16822996
    Loss of heterozygosity for loci on the long arm of chromosome 6 in human malignant melanoma.
    Millikin D, Meese E, Vogelstein B, Witkowski C, Trent J
    Cancer research. 1991 ; 51 (20) : 5449-5453.
    PMID 1680551
    Genomic alterations in primary cutaneous melanomas detected by metaphase comparative genomic hybridization with laser capture or manual microdissection: 6p gains may predict poor outcome.
    Namiki T, Yanagawa S, Izumo T, Ishikawa M, Tachibana M, Kawakami Y, Yokozeki H, Nishioka K, Kaneko Y
    Cancer genetics and cytogenetics. 2005 ; 157 (1) : 1-11.
    PMID 15676140
    Quantitative measures of the effect of the melanocortin 1 receptor on human pigmentary status.
    Naysmith L, Waterston K, Ha T, Flanagan N, Bisset Y, Ray A, Wakamatsu K, Ito S, Rees JL
    The Journal of investigative dermatology. 2004 ; 122 (2) : 423-428.
    PMID 15009725
    Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma.
    Nelson MA, Ariza ME, Yang JM, Thompson FH, Taetle R, Trent JM, Wymer J, Massey-Brown K, Broome-Powell M, Easton J, Lahti JM, Kidd VJ
    Cancer genetics and cytogenetics. 1999 ; 108 (2) : 91-99.
    PMID 9973934
    Malignant melanoma in patients with multiple endocrine neoplasia type 1 and involvement of the MEN1 gene in sporadic melanoma.
    Nord B, Platz A, Smoczynski K, Kytölä S, Robertson G, Calender A, Murat A, Weintraub D, Burgess J, Edwards M, Skogseid B, Owen D, Lassam N, Hogg D, Larsson C, Teh BT
    International journal of cancer. Journal international du cancer. 2000 ; 87 (4) : 463-467.
    PMID 10918183
    Cytoplasmic and nuclear accumulation of beta-catenin is rarely caused by CTNNB1 exon 3 mutations in cutaneous malignant melanoma.
    Omholt K, Platz A, Ringborg U, Hansson J
    International journal of cancer. Journal international du cancer. 2001 ; 92 (6) : 839-842.
    PMID 11351304
    The cytogenetics of human malignant melanoma and premalignant lesions. In: Malignant melanoma: biology, diagnosis and therapy.
    Parmiter AH, Nowell PC
    Nathalson L (eds)..
    Complete loss of HLA class I antigen expression on melanoma cells: a result of successive mutational events.
    Paschen A, Méndez RM, Jimenez P, Sucker A, Ruiz-Cabello F, Song M, Garrido F, Schadendorf D
    International journal of cancer. Journal international du cancer. 2003 ; 103 (6) : 759-767.
    PMID 12516095
    Nonrandom chromosome structural aberrations and oncogene loci in human malignant melanoma.
    Pedersen MI, Bennett JW, Wang N
    Cancer genetics and cytogenetics. 1986 ; 20 (1-2) : 11-27.
    PMID 3943054
    Genes involved in cell cycle G1 checkpoint control are frequently mutated in human melanoma metastases.
    Platz A, Sevigny P, Norberg T, Ring P, Lagerlf B, Ringborg U
    British journal of cancer. 1996 ; 74 (6) : 936-941.
    PMID 8826861
    Does the PITSLRE gene complex contribute to the pathogenesis of malignant melanoma of the skin? A study of patient-derived tumor samples?
    Poetsch M, Dittberner T, Woenckhaus C
    Cancer genetics and cytogenetics. 2001 ; 128 (2) : 181-182.
    PMID 11478303
    Evidence for three tumor suppressor loci on chromosome 9p involved in melanoma development.
    Pollock PM, Welch J, Hayward NK
    Cancer research. 2001 ; 61 (3) : 1154-1161.
    PMID 11221846
    Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC.
    Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T, Ruzicka T, Reifenberger G
    International journal of cancer. Journal international du cancer. 2002 ; 100 (5) : 549-556.
    PMID 12124804
    Growth factor and cytogenetic abnormalities in cultured nevi and malignant melanomas.
    Richmond A, Fine R, Murray D, Lawson DH, Priest JH
    The Journal of investigative dermatology. 1986 ; 86 (3) : 295-302.
    PMID 3745955
    The annual report to the nation on the status of cancer, 1973-1997, with a special section on colorectal cancer.
    Ries LA, Wingo PA, Miller DS, Howe HL, Weir HK, Rosenberg HM, Vernon SW, Cronin K, Edwards BK
    Cancer. 2000 ; 88 (10) : 2398-2424.
    PMID 10820364
    Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma.
    Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER
    The American journal of pathology. 1999 ; 154 (2) : 325-329.
    PMID 10027390
    Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic malignant melanomas.
    Rowan A, Bataille V, MacKie R, Healy E, Bicknell D, Bodmer W, Tomlinson I
    The Journal of investigative dermatology. 1999 ; 112 (4) : 509-511.
    PMID 10201537
    Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays.
    Stark M, Hayward N
    Cancer research. 2007 ; 67 (6) : 2632-2642.
    PMID 17363583
    Genomic structure, expression and mutational analysis of the P15 (MTS2) gene.
    Stone S, Dayananth P, Jiang P, Weaver-Feldhaus JM, Tavtigian SV, Cannon-Albright L, Kamb A
    Oncogene. 1995 ; 11 (5) : 987-991.
    PMID 7675459
    Cytogenetics of 158 patients with regional or disseminated melanoma. Subset analysis of near-diploid and simple karyotypes.
    Thompson FH, Emerson J, Olson S, Weinstein R, Leavitt SA, Leong SP, Emerson S, Trent JM, Nelson MA, Salmon SE
    Cancer genetics and cytogenetics. 1995 ; 83 (2) : 93-104.
    PMID 7553595
    Cutaneous melanoma.
    Thompson JF, Scolyer RA, Kefford RF
    Lancet. 2005 ; 365 (9460) : 687-701.
    PMID 15721476
    Identification of a recurring translocation site involving chromosome 6 in human malignant melanoma.
    Trent JM, Thompson FH, Meyskens FL Jr
    Cancer research. 1989 ; 49 (2) : 420-423.
    PMID 2642739
    Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans.
    Valverde P, Healy E, Jackson I, Rees JL, Thody AJ
    Nature genetics. 1995 ; 11 (3) : 328-330.
    PMID 7581459
    Virtually 100% of melanoma cell lines harbor alterations at the DNA level within CDKN2A, CDKN2B, or one of their downstream targets.
    Walker GJ, Flores JF, Glendening JM, Lin AH, Markl ID, Fountain JW
    Genes, chromosomes & cancer. 1998 ; 22 (2) : 157-163.
    PMID 9598804
    A genetic model of melanoma tumorigenesis based on allelic losses.
    Walker GJ, Palmer JM, Walters MK, Hayward NK
    Genes, chromosomes & cancer. 1995 ; 12 (2) : 134-141.
    PMID 7535086
    Expression of AP-2alpha, c-kit, and cleaved caspase-6 and -3 in naevi and malignant melanomas of the skin. A possible role for caspases in melanoma progression?
    Woenckhaus C, Giebel J, Failing K, Fenic I, Dittberner T, Poetsch M
    The Journal of pathology. 2003 ; 201 (2) : 278-287.
    PMID 14517845
    Genetic and epigenetic alterations of the APC gene in malignant melanoma.
    Worm J, Christensen C, Grnbaek K, Tulchinsky E, Guldberg P
    Oncogene. 2004 ; 23 (30) : 5215-5226.
    PMID 15133491
    Deletions and point mutations of p16,p15 gene in primary tumors and tumor cell lines.
    Yonghao T, Qian H, Chuanyuan L, Yandell DW
    Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih / Chinese Academy of Medical Sciences. 1999 ; 14 (4) : 200-205.
    PMID 12894891
    Cutaneous melanoma susceptibility and progression genes.
    de Snoo FA, Hayward NK
    Cancer letters. 2005 ; 230 (2) : 153-186.
    PMID 16297704
    Rising trends in the incidence of and mortality from cutaneous melanoma in the Netherlands: a Northwest to Southeast gradient?
    de Vries E, Schouten LJ, Visser O, Eggermont AM, Working Group of Regional Cancer Registries, Coebergh JW
    European journal of cancer (Oxford, England : 1990). 2003 ; 39 (10) : 1439-1446.
    PMID 12826048
    N-ras mutations in human cutaneous melanoma from sun-exposed body sites.
    van 't Veer LJ, Burgering BM, Versteeg R, Boot AJ, Ruiter DJ, Osanto S, Schrier PI, Bos JL
    Molecular and cellular biology. 1989 ; 9 (7) : 3114-3116.
    PMID 2674680
    Distinct chromosomal aberrations in sinonasal mucosal melanoma as detected by comparative genomic hybridization.
    van Dijk M, Sprenger S, Rombout P, Marres H, Kaanders J, Jeuken J, Ruiter D
    Genes, chromosomes & cancer. 2003 ; 36 (2) : 151-158.
    PMID 12508243
    Relevance of ultraviolet-induced N-ras oncogene point mutations in development of primary human cutaneous melanoma.
    van Elsas A, Zerp SF, van der Flier S, Krse KM, Aarnoudse C, Hayward NK, Ruiter DJ, Schrier PI
    The American journal of pathology. 1996 ; 149 (3) : 883-893.
    PMID 8780392


    This paper should be referenced as such :
    Castori, M ; Grammatico, P
    Skin Melanoma
    Atlas Genet Cytogenet Oncol Haematol. 2008;12(1):74-80.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other genes implicated (Data extracted from papers in the Atlas) [ 299 ]

    CCR9 CD109 CD151 CD200 CD248 CD47 CD59 CD82 CD9 CDC42
    S100A1 S100A2 S100A4 S100A7 S100B S100P SDCBP SEMA3F SH3PXD2A SHC4

    External links

    arrayMap Topo ( C44) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
    Other database
    Other database
    Other databaseICGC Data Portal - [SKCM-US] Skin Cutaneous melanoma - TCGA, US
    Other databasecBioPortal: Skin Cutaneous Melanoma (Broad, Cell 2012)
    Other databasecBioPortal: Skin Cutaneous Melanoma (TCGA, Provisional)
    Other databasecBioPortal: Skin Cutaneous Melanoma (Yale, Nature Genetics 2012)
    Other databaseMelanoma (My Cancer Genome)
    Other databaseSkin Cutaneous Melanoma (SKCM) TCGA Copy Number Portal
    Other databaseCutaneous melanoma ( intOGen )
    Other databaseCutaneous melanoma ( intOGen )
    Other databaseMalignant Melanoma (TCGA)(OASIS Portal)
    Other databaseSkin Cancer Overview - Disease Synopsis [canSAR]
    Other databaseSkin Cutaneous Melanoma [ Genomic Data Commons - NCI TCGA-SKCM]
    Disease databaseSkin: Melanoma
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Tue Oct 12 14:40:38 CEST 2021

    Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us