Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas

Satzger, Imke; Schaefer, T.; Kuettler, Uta; Broecker, Verena; Voelker, B.; Ostertag, Helmut; Kapp, Alexander; Gutzmer, Ralf

doi:10.1038/sj.bjc.6604791

Cited by 146 publications

(108 citation statements)

References 30 publications

(40 reference statements)

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“…We hypothesize here that the putative selection signatures that span several MYH genes most likely are a response to the need for animals to develop the resilience and endurance to travel long distances to access pastures and watering points. The KIT locus, and its interaction with the MITF locus, has been shown to confer resistance to melanosis and the ability to withstand UV radiation (Satzger et al, 2008;Pausch et al, 2012). Although we detected no obvious signals of selection around the KIT or MITF genes, we still identified selection signatures around genes that are involved in melanogenesis and melanoma angiogenesis.…”

Section: Discussionmentioning

confidence: 52%

Multiple genomic signatures of selection in goats and sheep indigenous to a hot arid environment

et al. 2015

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Goats and sheep are versatile domesticates that have been integrated into diverse environments and production systems. Natural and artificial selection have shaped the variation in the two species, but natural selection has played the major role among indigenous flocks. To investigate signals of natural selection, we analyzed genotype data generated using the caprine and ovine 50K SNP BeadChips from Barki goats and sheep that are indigenous to a hot arid environment in Egypt's Coastal Zone of the Western Desert. We identify several candidate regions under selection that spanned 119 genes. A majority of the genes were involved in multiple signaling and signal transduction pathways in a wide variety of cellular and biochemical processes. In particular, selection signatures spanning several genes that directly or indirectly influenced traits for adaptation to hot arid environments, such as thermo-tolerance (melanogenesis) (FGF2, GNAI3, PLCB1), body size and development (BMP2, BMP4, GJA3, GJB2), energy and digestive metabolism (MYH, TRHDE, ALDH1A3), and nervous and autoimmune response (GRIA1, IL2, IL7, IL21, IL1R1) were identified. We also identified eight common candidate genes under selection in the two species and a shared selection signature that spanned a conserved syntenic segment to bovine chromosome 12 on caprine and ovine chromosomes 12 and 10, respectively, providing, most likely, the evidence for selection in a common environment in two different but closely related species. Our study highlights the importance of indigenous livestock as model organisms for investigating selection sweeps and genome-wide association mapping.

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Section: Discussionmentioning

confidence: 52%

Multiple genomic signatures of selection in goats and sheep indigenous to a hot arid environment

et al. 2015

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“…15 KIT mutations and amplifications have been observed in varying frequencies in melanomas arising from different primary sites. [16][17][18] In addition, KIT protein expression or overexpression as detected by immunohistochemistry has been reported to show some correlation with KIT mutations or amplifications 16 but has been insufficient to predict response to KIT-targeted therapy with imatinib. 19 In a recent phase II study, response rates for metastatic melanomas treated with imatinib mesylate were 64.7% in patients with KIT exon 11 mutations, 40% for exon 17 mutations, and 33% for KIT amplifications.…”

Section: Discussionmentioning

confidence: 99%

Comparison of molecular abnormalities in vulvar and vaginal melanomas

et al. 2014

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Malignant melanoma of the vulva and vagina is relatively uncommon and accounts for o5% of all melanomas in women. The aim of our study was to establish the biological properties and evaluate potential therapeutic targets in these tumors. We collected a series of 65 cases from three centers and re-evaluated the tumor tissue for predominant growth pattern (superficial spreading, nodular, and mucosal lentiginous) and tumor thickness. KIT (CD117) expression was detected immunohistochemically. In addition, tumors were screened for BRAF, NRAS, and KIT mutations by PCR and DNA sequencing as well as for KIT amplifications by fluorescence in situ hybridization. None of the cases contained BRAF mutations. NRAS mutations and KIT amplifications were detected in similar frequency (B12%) in tumors of the vulva and vagina. In contrast, KIT mutations were present in 18% of primary melanomas of the vulva, but in none of the tumors arising in the vagina. Moderate or strong KIT protein expression was detected in 30 cases, including all tumors with KIT mutations and 6 of the 7 with KIT amplifications. In conclusion, BRAF mutations are virtually absent in melanomas originating from the vulva or vagina, whereas NRAS mutations and KIT amplifications occur in both locations. KIT mutations appear to be specific for melanomas of the vulva, suggesting that in spite of the anatomic proximity, the development of vulvar and vaginal melanomas involves different molecular alterations which may be targeted by novel treatment approaches.

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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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Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas

Cited by 146 publications

References 30 publications

Multiple genomic signatures of selection in goats and sheep indigenous to a hot arid environment

Multiple genomic signatures of selection in goats and sheep indigenous to a hot arid environment

Comparison of molecular abnormalities in vulvar and vaginal melanomas

NRAS and BRAF mutation frequency in primary oral mucosal melanoma

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