Distinct Sets of Genetic Alterations in Melanoma

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
New England Journal of Medicine (Impact Factor: 55.87). 12/2005; 353(20):2135-47. DOI: 10.1056/NEJMoa050092
Source: PubMed


Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light.
We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas.
We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89 percent accuracy. Eighty-one percent of melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway.
The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.

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Available from: Philip E Leboit, Sep 24, 2014
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    • "These last three subtypes are less common than SSM and NM in Caucasian populations, and their genetic aberrations seem to follow different patterns (Bastian, 2014; Curtin et al., 2005); they are mostly not discussed here for reasons of space. Likewise primary melanomas of other organs are not discussed here; the commonest is ocular melanoma, which again shows different patterns of genetic change from cutaneous melanoma (Bastian, 2014; Dono et al., 2014). "
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    • "Hyperactivation of PI3K/AKT/mTOR pathway in melanoma has been demonstrated to occur through mutations in NRAS or PTEN or by activating G protein-coupled receptors such as GRM1 [12] [13] [14]. We have shown that AKT is one of the downstream targets of GRM1, which promotes cellular transformation through autocrine (or possibly paracrine) activation regardless of PTEN or NRAS mutational status [15] [16] [17]. "
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    • "In contrast to the numerous mutational data in cutaneous melanomas, very limited data are available [23] [24] [25] [26] [27] [28], concerning either the full spectrum of mutational events affecting the MAPK/ERK, PI3K/AKT, and GNAQ/11 pathways in female genital tract melanomas or the DNA mismatch repair (MMR) status [29] in the same type of malignancy. To gain insight into the molecular genetics of melanoma of the female genital tract and to its DNA MMR status, in the present study we systematically investigated the mutational status of eight genes whose products are critically involved in the MAPK/ERK, PI3K/AKT, and GNAQ/11 pathways, such as BRAF, NRAS, HRAS, KRAS, c-KIT, PI3K, GNAQ, and GNA11, by employing either real-time PCR coupled with fluorescence melting curve analysis for mutation-specific PCR detection, or PCR followed by direct sequencing techniques, along with studies to determine the DNA MMR status using immunohistochemistry. "
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