Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas

Ashida, Atsuko; Takata, Minoru; Murata, Hiroshi; Kido, Koichi; Saida, Toshiaki

doi:10.1002/ijc.24048

Cited by 127 publications

(128 citation statements)

References 33 publications

(64 reference statements)

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“…In Mutation and up-regulation of c-kit have been studied in mucosal melanomas (14,15,22,23). In particular, activating mutations have been correlated with increased c-kit protein expression (13).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

NRAS and BRAF mutation frequency in primary oral mucosal melanoma

et al. 2011

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“…The primer sequences are listed in Supplementary Table S2. PCR conditions have been described previously (5,13,15,(23)(24)(25). We purified PCR products with QIAquick (Qiagen), and directly sequenced them using Big Dye Terminator sequencing chemistry on an ABI 3130 automated sequencer (Applied Biosystems).…”

Section: Dna Preparation and Mutation Screeningmentioning

confidence: 99%

“…Quantitative real-time PCR was performed as described previously (15,23), using ribonuclease P (RNase P) as a control gene. Relative copy numbers were calculated using the DDC t method (as detailed in Supplementary Table S2).…”

Section: Kit Gene Amplification Analysis By Real-time Pcrmentioning

confidence: 99%

“…Recently, Curtin and colleagues, who examined 102 primary melanomas excised from various anatomical sites, found mutations and/or copy number increases of KIT in 39% of mucosal melanomas, 36% of acral melanomas, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on nonglabrous skin without CSD (5). Other recent studies also identified oncogenic KIT mutations in several melanoma cohorts (4,(12)(13)(14)(15). These findings indicate that KIT is an important oncogene in melanomas of mucosa, acral skin, and skin with CSD.…”

Section: Introductionmentioning

confidence: 99%

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Large-Scale Analysis of KIT Aberrations in Chinese Patients with Melanoma

Kong

Zhu

et al. 2011

Clinical Cancer Research

217

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Purpose: KIT aberrations were described in acral and mucosal melanomas in largely Caucasian populations. Asian populations are more prone to develop acral and mucosal than cutaneous melanomas, and may harbor a high frequency of KIT aberrations.Experimental Design: Melanoma subtypes (n ¼ 502) were analyzed histologically to determine melanoma subtype. Tissue samples were analyzed for mutations in exons 9, 11, 13, 17, and 18 of KIT gene in genomic DNA by PCR amplification and Sanger sequencing. The copy numbers of the KIT gene were analyzed by quantitative PCR, and protein expression levels of KIT (CD117) were determined by immunohistochemistry.Results: The most common melanoma subtypes were acral (38.4%) and mucosal (33.3%) melanomas in this population. The overall incidence of somatic mutations within the KIT gene was 10.8% (54/502), and all subtypes of melanoma contained KIT mutations. Increases in KIT gene copy numbers were correlated to CD117 overexpression. The genetic mutations of KIT were unrelated to the age, gender, stage, thickness, and ulceration of primary melanomas. Importantly, the overall survival of melanoma patients with KIT mutations (P ¼ 0.001) or with KIT aberrations (mutation plus amplification, P ¼ 0.0002) was significantly shorter than that of patients without such alterations.Conclusion: In China, the prevalent melanomas are acral and mucosal melanomas. KIT mutations are detected in all melanoma subtypes. Our study suggests that increases in KIT gene copy numbers, but not KIT mutations, may be correlated to CD117 overexpression. For the first time, our study suggests that genetic KIT aberration is an adverse prognostic factor for melanoma. Clin Cancer Res; 17(7); 1684-91. Ó2011 AACR.

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“…39 Abnormalities in KIT, the receptor tyrosine kinase immediately upstream of RAS and PI3K, are found in roughly 27% of mucosal, 24% of acral, and 21% of melanomas on chronically sun-damaged skin, but are seldom found in melanomas on skin without chronic sun damage. [47][48][49][50][51] KIT stimulates both the MAPK and PI3K-AKT pathways; thus, mutations in KIT lead to deregulated growth and survival. 52 As KIT stimulates MITF, c-KIT aberrations can overactivate MITF, and cause proliferation and reduced apoptosis.…”

Section: Pathophysiology: Sharing Of Signal Transduction Pathways mentioning

confidence: 99%