C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma

Rivera, Rosario Santos; Nagatsuka, Hitoshi; Gündüz, Mehmet; Cengiz, Beyhan; Gündüz, Esra; Siar, Chong Huat; Tsujigiwa, Hidetsugu; Tamamura, Ryo; Han, Kok Ng; Nagai, Noriyuki

doi:10.1007/s00428-007-0524-2

Cited by 157 publications

(138 citation statements)

References 39 publications

(59 reference statements)

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“…Our results regarding the limited utility of CD117 staining in ocular melanoma are in accordance with the majority of data from other melanoma subtypes. Studies of acral, mucosal, and cutaneous melanomas by Beadling et al, 8 Curtin et al, 9 and Rivera et al 28 have all shown limited correlation between CD117 staining intensity and KIT mutational status. Although Torres-Cabala et al 15 recently demonstrated a significant correlation between KIT mutational status and the percentage of CD117-positive tumor cells, irrespective of staining intensity, in their large series of acral, lentiginous, and mucosal melanomas, their positive predictive value was still low (14%).…”

Section: Discussionmentioning

confidence: 98%

KIT mutations in ocular melanoma: frequency and anatomic distribution

et al. 2011

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KIT mutations are known to occur in B15% of chronic sun damaged cutaneous, mucosal, and acral melanomas. Melanomas with demonstrated activating mutations in KIT or platelet-derived growth factor receptor A (PDGFRA) may benefit from treatment with tyrosine kinase inhibitors. Currently, the limited data regarding KIT mutational status in ocular melanoma suggest that activating mutations are extremely rare. PDGFRA mutational status in ocular melanoma has not been determined. Seventy-five ocular melanomas (53 choroidal, 6 iris, 11 ciliary body, and 5 conjuctival) were selected from the files of the Department of Ophthalmology. High-resolution melting curve analysis and sequencing were performed to detect mutations in KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18. Results of mutational analysis were correlated with anatomical site and KIT (CD117) immunohistochemistry. Eight of 75 (11%) ocular melanomas contained mutations in either the KIT or PDGFRA gene. Five of 53 (9%) choroidal melanomas were associated with mutations (KIT exon 11 ¼ 3; KIT exon 17 ¼ 1; PDGFRA intron 18 ¼ 1). Two of six (33%) iris melanomas and a single (9%) ciliary body melanoma harbored KIT exon 11 mutations. No mutations were identified in conjunctival melanomas. The distribution of KIT and PDGFRA mutations by ocular melanoma anatomical site did not reach statistical significance (P ¼ 0.393) CD117 positivity was not predictive of KIT mutational status as only 6 of 58 (10%) CD177-positive tumors harbored KIT mutations. In addition, a KIT exon 17 mutation was identified in one CD117-negative tumor. KIT and PDGFRA mutations do occur in ocular melanomas at a frequency (11%) that is similar to acral and mucosal melanomas. Limited correlation of CD117 positivity with mutational status suggests that all ocular melanomas should undergo mutational analysis to determine if imatinib therapy is appropriate.

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Section: Discussionmentioning

confidence: 98%

KIT mutations in ocular melanoma: frequency and anatomic distribution

et al. 2011

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“…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.…”

mentioning

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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“…MITF expression has been found in 40 to 91% of mucosal melanomas of the head and neck (Morris et al, 2008;Prasad et al, 2001). High rates of c-kit protein expression has been reported for mucosal melanomas and this immunohistochemical expression is associated with c-kit mutation (Rivera et al, 2008). A review of the literature report that 14% of mucosal melanomas harbor activating C-KIT mutations; 5% showed BRAF mutation and 14% oncogenic mutations in NRAS, which is much lower than the reported BRAF prevalence (56 to 59%) in cutaneous melanomas (Tacastacas et al, 2014;Cohen et al, 2004).…”

Section: Geneticsmentioning

confidence: 93%

“…Unlike cutaneous melanoma, BRAF mutation are infrequent and KIT mutation seem to be frequently altered (Lopez et al, in press;Soma et al, 2014;Kerr et al 2012;Buery et al, 2011;Junkins-Hopkins, 2010). (Tacastacas et al, 2014;Rivera et al, 2008).…”

Section: Genes Involved and Proteinsmentioning

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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C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma

Cited by 157 publications

References 39 publications

KIT mutations in ocular melanoma: frequency and anatomic distribution

KIT mutations in ocular melanoma: frequency and anatomic distribution

NRAS and BRAF mutation frequency in primary oral mucosal melanoma

Head and Neck: Primary oral mucosal melanoma

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