Antonescu CR, Busam KJ, Francone TD, Wong GC, Guo T, Agaram NP et al.L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer 121:257-264

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
International Journal of Cancer (Impact Factor: 5.09). 07/2007; 121(2):257-64. DOI: 10.1002/ijc.22681
Source: PubMed


Activating mutations in either BRAF or NRAS are seen in a significant number of malignant melanomas, but their incidence appears to be dependent to ultraviolet light exposure. Thus, BRAF mutations have the highest incidence in non-chronic sun damaged (CSD), and are uncommon in acral, mucosal and CSD melanomas. More recently, activating KIT mutations have been described in rare cases of metastatic melanoma, without further reference to their clinical phenotypes. This finding is intriguing since KIT expression is downregulated in most melanomas progressing to more aggressive lesions. In this study, we investigated a group of anal melanomas for the presence of BRAF, NRAS, KIT and PDGFRA mutations. A heterozygous KIT exon 11 L576P substitution was identified in 3 of 20 cases tested. The 3 KIT mutation-carrying tumors were strongly immunopositive for KIT protein. No KIT mutations were identified in tumors with less than 4+ KIT immunostaining. NRAS mutation was identified in one tumor. No BRAF or PDGFRA mutations were identified in either KIT positive or negative anal melanomas. In vitro drug testing of stable transformant Ba/F3 KIT(L576P) mutant cells showed sensitivity for dasatinib (previously known as BMS-354825), a dual SRC/ABL kinase inhibitor, and imatinib. However, compared to an imatinib-sensitive KIT mutant, dasatinib was potent at lower doses than imatinib in the KIT(L576P) mutant. These results suggest that a subset of anal melanomas show activating KIT mutations, which are susceptible for therapy with specific kinase inhibitors.

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Available from: Peter Besmer, Mar 09, 2015
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    • "Some authors also noticed different c-kit overexpression between mucosal melanomas in various sites. c-kit expression has been found in 88% of oral mucosa melanoma, whereas only 12% of anal mucosa melanomas harbor this feature.26,27 These findings, together with the discovery of distinct GNAQ or GNA11 implication in 80% of uveal melanomas, support the idea of the importance of the molecular classification of melanomas.7,29,30 "
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    • "Several studies have shown that BRAF mutations are uncommon in mucosal melanomas, with reported frequencies ranging from 0 to approximately 10% [11] [25] [26] [39] [41]. In line with this, we did not detect BRAF mutations in our series of female urogenital tract melanomas. "
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    ABSTRACT: The aim of this study was to evaluate a series of primary melanomas of the female urogenital tract for oncogenic mutations in KIT, NRAS and BRAF in order to identify patients who may be amenable to targeted therapy. We reviewed twenty-four cases of female urogenital tract melanomas and used Sanger sequencing analysis for the detection of oncogenic mutations in exons 9, 11, 13, and 17 of KIT; exons 2 and 3 of NRAS; and exon 15 of BRAF. Twenty-four patients were included: fourteen vaginal melanomas, four cervical melanomas, five urethral melanomas and one vulvar melanoma. NRAS mutations (4/24, 21%) were more prevalent than KIT mutations (1/24, 4%), while BRAF mutations were absent. Three of four NRAS mutations were present in vaginal melanomas (21%), mainly affecting codon 61 (3/4). They were mutually exclusive with the KIT mutation. The KIT mutation was present in a vaginal melanoma and affected exon 17. Melanomas of the female urogenital tract relatively commonly harbor mutations in NRAS; this makes NRAS an interesting therapeutic target for these patients in the advanced setting. KIT mutations were rare in our study in contrast to some previous reports. We cannot exclude that anatomical site-related differences and/or population related differences in KIT mutation frequency exist within urogenital tract melanomas.
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    • "Despite the high frequency of KIT expression in thymic cancer, only 9% (between the 80 collectively analyzed) harbored KIT mutations [70] [73]. In particular V560 deletion [70] [75] (like in GISTs) and Y553N substitution, both in exon 11, are imatinib – sensitive; instead D820Y substitution leads to imatinib-resistance. H697Y substitution in exon 14 is associated with in vitro higher sensitivity to sunitinib than to imatinib [70], while L576P substitution is imatinib and sunitinib – sensitive [70] [76]. On the other hand mutations that confer responsiveness to sorafenib are D820E substitution in exon 17 and P577–579 deletion in exon 11 [77] [78]. "
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