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Melanoma Treatment (Professional) (cont.)

Cellular and Molecular Classification of Melanoma

Following is a list of clinicopathologic cellular subtypes of malignant melanoma. These should be considered descriptive terms of historic interest only as they do not have independent prognostic or therapeutic significance.

  • Superficial spreading.
  • Nodular.
  • Lentigo maligna.
  • Acral lentiginous (palmar/plantar and subungual).
  • Miscellaneous unusual types:
    • Mucosal lentiginous (oral and genital).
    • Desmoplastic.
    • Verrucous.

Molecular characterization of melanoma is an active area of research. Activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) gene, first reported in 2002, are the most frequent mutation in cutaneous melanoma. Approximately 40% to 60% of malignant melanomas harbor a single nucleotide transversion. The majority have a mutation that results in a substitution from valine to glutamic acid at position 600 BRAF (V600E); less frequent mutations include valine 600 to lysine or arginine residues (V600K/R).[1] Drugs that target this mutation by inhibiting BRAF are under evaluation in clinical trials. One such drug, vemurafenib, was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of unresectable or metastatic melanoma in patients who test positive for the BRAF mutation as detected by an FDA-approved test (e.g., cobas® 4800 BRAF V600 Mutation Test).

In smaller subsets of cutaneous melanoma, other activating mutations have been described, including NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], c-KIT, and CDK4 (cyclin-dependent kinase 4).

  • Approximately 15% to 20% of melanomas harbor an oncogenic NRAS mutation.[2,3]
  • A c-KIT mutation, or increased copy number, is associated with mucosal and acral melanomas (which comprise 6% to 7% of melanomas in Caucasians but are the most common subtype in the Asian population).[4,5,6]
  • CDK4 mutations have been described in approximately 4% of melanomas and are also more common in acral and mucosal melanomas.[7,8]

Drugs developed to target these mutations are currently in clinical trials. Additional oncogenes and tumor-suppressor gene candidates currently under evaluation include P13K, AKT, P53, PTEN, mTOR, Bcl-2, MITF.

Uveal melanomas differ significantly from cutaneous melanomas; in one series, 83% of 186 uveal melanomas were found to have a constitutively active somatic mutation in GNAQ or GNA11.[9,10]


  1. Pollock PM, Meltzer PS: A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2 (1): 5-7, 2002.
  2. Edlundh-Rose E, Egyházi S, Omholt K, et al.: NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res 16 (6): 471-8, 2006.
  3. Goel VK, Lazar AJ, Warneke CL, et al.: Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol 126 (1): 154-60, 2006.
  4. Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008.
  5. Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011.
  6. Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011.
  7. Curtin JA, Fridlyand J, Kageshita T, et al.: Distinct sets of genetic alterations in melanoma. N Engl J Med 353 (20): 2135-47, 2005.
  8. Stark M, Hayward N: Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays. Cancer Res 67 (6): 2632-42, 2007.
  9. Van Raamsdonk CD, Bezrookove V, Green G, et al.: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457 (7229): 599-602, 2009.
  10. Van Raamsdonk CD, Griewank KG, Crosby MB, et al.: Mutations in GNA11 in uveal melanoma. N Engl J Med 363 (23): 2191-9, 2010.
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