<i>GAB2</i> Amplifications Refine Molecular Classification of Melanoma

Chernoff, Karen A.; Bordone, Lindsey; Horst, Basil A.; Simon, Katherine; Twadell, William; Lee, Keagan; Cohen, Jonah N.; Wang, Shuang; Silvers, David N.; Brunner, Georg; Çelebi, Jülide Tok

doi:10.1158/1078-0432.ccr-09-0280

Cited by 53 publications

(48 citation statements)

References 14 publications

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“…It has been reported that NRAS and BRAF mutations are mutually exclusive (15,19). Interestingly, the case with the BRAF missense mutation had wild-type c-kit (13) suggesting that the c-kit mutation is independent from the BRAF mutation.…”

Section: Discussionmentioning

confidence: 95%

“…NRAS and BRAF mutations have been reported in subsets of mucosal melanomas, but most reports focused on combined mucosal sites (9,(16)(17)(18)(19). Most reports have claimed that NRAS and BRAF mutations are infrequent, justifying that mucosal melanoma is distinct from its cutaneous counterpart.…”

Section: Introductionmentioning

confidence: 99%

“…The MAPK pathway together with the phosphoinositide 3-kinase cascade (PI3K) can be triggered by activation of c-kit leading to the recruitment of signaling proteins involved in tremendous cell proliferation and survival (12). Mutations in c-kit have been identified in mucosal melanomas rendering c-kit as a promising molecular target (13)(14)(15).NRAS and BRAF mutations have been reported in subsets of mucosal melanomas, but most reports focused on combined mucosal sites (9,(16)(17)(18)(19). Most reports have claimed that NRAS and BRAF mutations are infrequent, justifying that mucosal melanoma is distinct from its cutaneous counterpart.…”

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confidence: 99%

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NRAS and BRAF mutation frequency in primary oral mucosal melanoma

et al. 2011

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Abstract. Oral mucosal melanoma (OMM) is a fatal sarcoma of unknown etiology. Histological morphology and genetic events are distinct from those of its cutaneous counterpart. Mutation and up-regulation of c-kit has been identified in OMM which may activate downstream molecules such as RAS and RAF. These molecules are involved in the mitogenactivated protein kinase (MAPK) pathway leading to tremendous cell proliferation and survival. NRAS and BRAF mutation and protein expression have been studied in other melanoma subtypes. The purpose of this study was to determine RAS protein expression and NRAS and BRAF mutation in 18 primary OMM cases using immunohistochemistry and mutation analysis. Results showed that RAS is intensely expressed in both in situ and invasive OMMs. However, NRAS mutation was only observed in 2/15 polymerase chain reaction (PCR) amplified cases both of which were silent mutations. On the other hand, BRAF missense mutations were observed only in 1/15 cases with PCR amplification. NRAS and BRAF mutations were independent from previously reported c-kit mutations. The classical V600E BRAF mutation was not found; instead a novel V600L was observed suggesting that the oncogenic event in OMM is different from that in skin melanoma. The low frequency of NRAS and BRAF mutations indicate that these genes are not common, but probable events in OMM pathogenesis, most likely independent of c-kit mutation. IntroductionOral mucosal melanoma (OMM) is a malignant tumor in the oral cavity characterized by adjoining proliferation of atypical melanocytes and alteration of their normal functions. Although OMM is a rare tumor observed in 0.5% of oral malignancies and 0.2-8% of all melanomas, it has an aggressive behavior with poor prognosis (1,2). Precursor lesions have not been clearly elucidated but the onset of atypical melanocytic proliferation may be the earliest indication of its development (1,3). OMM based on histological examination can be classified as in situ, invasive and the combination of both, the latter being the most commonly observed (1,4).Mitogen-activated protein kinase (MAPK) is the most common pathway described in oncogenic events during the progression of melanoma (5-8). One of the molecules that participate in this signal transduction cascade is RAS encoded by the RAS gene consisting of HRAS, KRAS and NRAS. Another molecule that leads to the activation of MAPK is RAF consisting of ARAF, BRAF and CRAF. Frequent mutations in NRAS and BRAF have been observed in cutaneous melanoma (9-11). The MAPK pathway together with the phosphoinositide 3-kinase cascade (PI3K) can be triggered by activation of c-kit leading to the recruitment of signaling proteins involved in tremendous cell proliferation and survival (12). Mutations in c-kit have been identified in mucosal melanomas rendering c-kit as a promising molecular target (13)(14)(15).NRAS and BRAF mutations have been reported in subsets of mucosal melanomas, but most reports focused on combined mucosal sites (9,(16)(17)(18)(19). Most reports have cla...

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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NRAS and BRAF mutation frequency in primary oral mucosal melanoma

et al. 2011

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“…Notably, although the BRAF gene is mutated in approximately 50% of melanomas from hair-bearing skin, BRAF is only mutated in approximately 16% of acral melanomas, and whereas KIT is not mutated in melanoma from hair-bearing skin, it is mutated in approximately 20% of acral melanomas (Curtin et al, 2006). Furthermore, focal gene amplifications involving the regions that encode GAB2 (Chernoff et al, 2009), CCND1 (Sauter et al, 2002) and CDK4 (Curtin et al, 2005) in particular appear to be more prevalent in acral melanoma than in hair-bearing skin melanoma. These studies have demonstrated that cutaneous melanomas from hair-bearing and acral skin are genetically distinct diseases, and accordingly, at least in some studies, it has been shown that acral melanoma is inherently more aggressive and has a poorer prognosis than melanoma from hair-bearing skin (Bradford et al, 2009).…”

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confidence: 99%

Genomic characterisation of acral melanoma cell lines

Furney

Turajlic

Fenwick

et al. 2012

Pigment Cell Melanoma Res

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“…Among the 23 acral and mucosal melanomas studied, copy number changes in GAB2 were found in 26% and KIT in 13% (3 of 23) of the cases. Mutations in BRAF were identified in 30% (7 of 23) of the cases and NRAS, in 4% (1 of 23) of the cases (Chernoff et al, 2009).…”

Section: Cytogenetics Morphologicalmentioning

confidence: 99%

Head and Neck: Primary oral mucosal melanoma

Coutinho‐Camillo¹,

Lourenço²,

Soares³

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Primary Oral Mucosal Melanoma (POMM) is an aggressive and rare disease that involves mostly the hard palate and upper gingiva, followed by mandibular gingiva, lip mucosa, and other oral sites. POMM develops primarily between the 5th and 8th decades of life and most studies report a similar distribution between males and females. In contrast to cutaneous melanomas, the risk factors and pathogenesis are poorly understood. However, genetic profiling of mucosal melanomas have identified a number of altered genes, such as KIT, BRAF and N-RAS, suggesting that molecular pathways like the mitogen-activated protein kinase (MAPK) pathway (RAS/MEK/ERK) and the phosphotidylinositol-3-kinase-PTEN pathway (PI3K/AKT/PTEN/mTOR) might be used for potential targeted therapy.

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GAB2 Amplifications Refine Molecular Classification of Melanoma

Cited by 53 publications

References 14 publications

NRAS and BRAF mutation frequency in primary oral mucosal melanoma

NRAS and BRAF mutation frequency in primary oral mucosal melanoma

Genomic characterisation of acral melanoma cell lines

Head and Neck: Primary oral mucosal melanoma

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