Cellular and Molecular Classification of Melanoma
The descriptive terms for clinicopathologic cellular subtypes of malignant melanoma should be considered of historic interest only; they do not have independent prognostic or therapeutic significance. The cellular subtypes are the following:
- Superficial spreading.
- Lentigo maligna.
- Acral lentiginous (palmar/plantar and subungual).
- Miscellaneous unusual types:
- Mucosal lentiginous (oral and genital).
Identification of activating mutations in the mitogen-activated protein (MAP) kinase pathway served as a catalyst to develop a molecular classification of melanoma. Such a classification provides potential drug targets, directions for future clinical trials, and the ability to select patients for targeted therapies.
BRAF gene mutations
BRAF (V-raf murine sarcoma viral oncogene homolog B1) genes, first reported in 2002, are the most frequent mutations in cutaneous melanoma. Approximately 40% to 60% of malignant melanomas harbor a single nucleotide transversion in BRAF. Most 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).
Drugs that target this mutation by inhibiting BRAF are under evaluation in clinical trials. 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).
Other gene mutations
In smaller subsets of cutaneous melanoma, other activating mutations have been described, including the following:
- NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog): Approximately 15% to 20% of melanomas harbor an oncogenic NRAS mutation.[2,3]
- c-KIT: A c-KIT mutation, or increased copy number, is associated with mucosal and acral melanomas (which comprise 6%–7% of melanomas in whites but are the most common subtype in the Asian population).[4-6]
- CDK4 (cyclin-dependent kinase 4): 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, and 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] (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)
- Pollock PM, Meltzer PS: A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2 (1): 5-7, 2002. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011. [PUBMED Abstract]
- Curtin JA, Fridlyand J, Kageshita T, et al.: Distinct sets of genetic alterations in melanoma. N Engl J Med 353 (20): 2135-47, 2005. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Van Raamsdonk CD, Griewank KG, Crosby MB, et al.: Mutations in GNA11 in uveal melanoma. N Engl J Med 363 (23): 2191-9, 2010. [PUBMED Abstract]