C-kit, B-raf, and N-ras mutations in melanoma subtypes.

Abstract

e19037 Background: The recent understanding of melanomas’ molecular pathways improved their classification and clinical strategies. Initial studies showed that B-Raf/N-Ras mutations (respectively V600E and Q61) are the most frequent alterations being present in 70 to 80% of melanomas, characterizing non Chronic Sun-induced Damage skins (CSD). These include Superficial Spreading Melanomas (SSM) and Nodular Melanomas (NM). Other studies showed that c-Kit mutations are present at low rate (20-40%) in Acro-Lentiginous Melanomas (ALM), Mucous Melanomas (MM) and in melanomas arising on CSD skins. C-kit mutation pattern is complex with four exons being affected leading to numerous mutations. Because c-Kit targeted therapy is a critical clinical issue, we aimed to identify the most frequent mutations to propose appropriate screening test and adapted therapy. Methods: 186 melanoma samples corresponding to an homogeneous white-caucasian population (Brittany, France) were screened. c-Kit exons 11, 13,17 and 18 were sequenced, c-Kit copy number was quantified by q-PCR and level of c-Kit determined by immunohistochemistry (CD117). Samples were also analyzed for B-Raf mutations (codon 464, 466, 469, 600) and for N-Ras mutations (codon 12, 13, 61) by pyrosequencing. Results: Detectedmutations are shown in the table. Uveal melanomas (n=13) were never mutated. These mutations were never overlaped and comparable profiles were obtained between the primary tumour, nodes or metastatic lesions from a same patient. Conclusions: C-Kit mutations are much less common than in other previously described populations especially for MM or ALM. B-Raf/N-Ras mutations appeared also less frequent than waited in non-CSD , reaching 46% in SSM. Interestingly our population presents a high incidence of N-Ras mutations, especially in SSM and NM. Screening of B-Raf/N-Ras mutations is fundamental not only for SSM but also for NM, CSD and ALM for prescribing targeted therapies such as MEK-inhibitors. [Table: see text]