Despite the large body of mutational data available for melanoma and epidemiological studies linking this cancer to ultraviolet radiation (UVR), the fundamental carcinogenic mechanisms involved in melanoma remain largely unknown. To this end, we systematically reviewed, extracted, and analyzed mutational data from the extant melanoma literature in an effort to gain more insight into its early pathogenic events. We searched PubMed (1966-January 2006) using the words "mutation" AND "melanoma" in the title or abstract. Out of 2,095 returned results, there were 203 eligible studies that were subsequently analyzed. We cataloged 8,201 somatic and cultured melanoma specimens and annotated 2,041 reported somatic sequence variants. The single BRAF c.1799T>A (p.Val600Glu) alteration is the most prevalent variant while other A:T>T:A transversions were uncommon. Four highly-recurrent, non-ultraviolet B (UVB) changes account for most of the NRAS and BRAF variants. CDKN2A, PTEN/MMAC1, and TP53 harbored statistically higher rates of UVB signature changes (64.2%, 52.4%, and 69.2%, respectively) than oncogenic loci (NRAS: 15.3% and BRAF: 2.4%). More specifically, cutaneous melanomas showed a significantly higher proportion of UVB signature mutations at both TP53 and CDKN2A when compared to non-skin cancers using data from their respective locus-specific databases. Superficial spreading and nodular melanomas had the highest rates of BRAF (53.4%) and NRAS (28.0%) mutations. In melanoma, there is sufficient mutational evidence to support a role for direct UVB participation, especially at TP53 and CDKN2A. For oncogenes, the role for UVB is less clear since functionally-activating changes are uncommon and are subject to sequence constraints.
"Although UV radiation is considered as the main cause of malignant melanoma concerning the sun-exposed body sites  , it seems that other mechanisms are also capable of initiating melanocyte malignant transformation, leading to tumours with different clinical behaviour. Specifically, malignant melanoma of the female genital tract is biologically aggressive, difficult to manage, carrying a poor prognosis and a high incidence of recurrence, while its pathogenesis is still obscure and to a large extend, independent of UV radiation . "
[Show abstract][Hide abstract] ABSTRACT: Mucosal melanomas exhibit discrete genetic features compared to cutaneous melanoma. Limited studies on gynecological melanomas revealed significant heterogeneity and low mutational burden. To gain further insight into their genetics and DNA repair efficiency, we systematically investigated the status of eight genes whose products are critically involved in the MAPK/ERK, PI3K/AKT, and GNAQ/11 pathways, including BRAF, NRAS, HRAS, KRAS, c-KIT, PI3K, GNAQ, and GNA11, in a series of 16 primary gynecological melanomas, covering all anatomical locations, ranging from stages I to III. Analysis either by real-time PCR coupled with fluorescence melting curve analysis or by PCR followed by direct sequencing, along with studies for DNA mismatch repair status using immunohistochemistry, disclosed that 15 out of the 16 cases displayed wild-type genotypes, with a single case of vulvar primary melanoma, harboring the activating mutation BRAF(V600E). Investigations on whether this could reflect partly an efficient mismatch repair (MMR) mechanism were confirmed by normal expression of hMLH1 and hMSH2, suggesting that the lack of mutations could be explained by the operation of alternative pathogenetic mechanisms modulating downstream effectors of the signaling pathways. Our data suggest the presence of additional genetic components and provide the impetus for systematic approaches to reveal these yet unidentified genetic parameters.
BioMed Research International 01/2015; 2015:303791. DOI:10.1155/2015/303791 · 3.17 Impact Factor
"Consistent with previous studies by ourselves and others, BRAF V600 mutations were more frequent in cutaneous melanomas than in acral and mucosal melanomas.(Hocker and Tsao, 2007; Jakob et al., 2012) The rates of BRAF V600 , BRAF Non-V600 , NRAS, and TP53 mutations in melanomas with an unknown primary tumor were nearly identical to the rates observed in cutaneous melanomas. This result is also consistent with similar rates observed between unknown primary melanomas and melanomas with a known cutaneous primary in"
[Show abstract][Hide abstract] ABSTRACT: The management of melanoma has evolved due to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAF(V600)(36%), NRAS (21%), TP53 (16%), BRAF(Non-V600)(6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent event in tumors with BRAF(V600)and NRAS mutations. Melanomas with BRAF(Non-V600)mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAF(V600) mutations (1.6%). The prevalence of BRAF(V600) and KIT mutations were significantly associated with melanoma subtypes, and BRAF(V600) and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAF(V600)and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.Journal of Investigative Dermatology accepted article preview online, 22 August 2014; doi:10.1038/jid.2014.366.
"In most tumors, p53 is mutated, which not only disables its tumor suppressor activity, but can confer an oncogenic potential. In melanoma, WT p53 is found inactivated in some way in approximately 90% of cases with approximately 10% carrying disabling point mutations (Hocker and Tsao, 2007) although this number could be as high as 19% (Hodis et al., 2012). Based on the relatively low p53 mutational rate and the success of BRAFV600E inhibitors, there has been great interest in re-examining the old paradigms of p53 activation during conventional chemotherapy to determine whether the powerful antitumor functions of WT p53 can be harnessed for clinical benefit. "
[Show abstract][Hide abstract] ABSTRACT: Melanoma is the sixth most common cancer in the United States with the numbers of annual cases increasing faster than any other tumor type. Approximately 50% of melanomas harbor oncogenic BRAF mutations, 90% of which are BRAFV600E. Recent U.S. Food and Drug Administration (FDA) approval of the selective BRAFV600E inhibitor, Zelboraf (vemurafenib), has inspired rapid development of new targeted therapeutic strategies for melanoma. Subsequently, the first FDA approved combination of molecularly targeted cancer therapies has emerged with GlaxoSmithKline's Taflinar (dabrafenib) and Mekinist (trametinib) that inhibit BRAFV600E and the primary downstream target, MEK (mitogen-activated protein kinase kinase), respectively. Since BRAF and MEK function within the same oncogenic RAS pathway, there is much anticipation about forthcoming clinical trials investigating molecularly targeted combination therapies that attack two or more different pathways. This article is protected by copyright. All rights reserved.
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