Evaluation of MAP-Kinase Pathway in Sinonasal Melanomas
Christopher P Kragel, Tatyana Isayeva, Patricia DeVilliers, Aleodor Andea. University of Alabama at Birmingham, Birmingham, AL
Background: Most melanocytic proliferations are characterized by an activated MAP-kinase pathway as a result of activating mutations in either NRAS, HRAS, BRAF, GNAQ or KIT genes. The frequency of these mutations varies across different melanoma variants and sites. For example, NRAS and BRAF mutations being far less common and KIT mutations more frequent in melanomas arising in acral compared to non-acral sites, respectively. Mucosal melanomas arising in the head and neck represent 1% of all melanomas and have a median survival of only 2 years. In this study we aimed to investigate the activation status of BRAF, NRAS, GNAQ and KIT gene protein products in series of sinonasal melanomas to better characterize the molecular pathology of this rare but deadly malignancy.
Design: An interrogation of the UAB pathology database identified 8 sinonasal melanomas that had adequate tissue for study. Histologic confirmation of the melanoma was performed prior to further experiments. Following DNA extraction from formalin-fixed paraffin-embedded tissue, PCR was performed with primers specific for exons 15, 5 and 3 of BRAF, GNAQ and NRAS genes, respectively. Direct sequencing was performed and the status of codon 600 of BRAF, codon 61 of NRAS, and codon 209 of GNAQ genes, and the most common sites for activating mutations in melanoma was evaluated. Additionally, we evaluated c-kit expression by immunohistochemistry (IHC).
Results: Only one case (12.5%) showed V600E BRAF gene mutation and all eight were wild type for both the GNAQ and NRAS genes (See Table). By IHC, c-kit showed focal staining in 4 cases, with weak to moderate intensity. Due to the lack of c-kit expression it is unlikely to be involved in the pathophysiology of these lesions.
|Case #||Age at Dx.||Sex||Location||BRAF codon 600||GNAQ codon 209||NRAS codon 61||c-kit expression by IHC|
|1||73||M||R Nasal Cavity||wt||wt||wt||5% at 1+|
|2||77||M||L Nasal Cavity||wt||wt||wt||No Staining|
|3||73||M||R Nasal Cavity||wt||wt||wt||No Staining|
|4||74||F||L Nasal Cavity||wt||wt||wt||20% at 2+|
|5||60||M||R Maxillary Sinus||wt||wt||wt||No Staining|
|6||63||M||R Nasal Cavity||wt||wt||wt||2% at 1+|
|7||41||M||L Ethmoid and Sphenoid Sinus||V600E||wt||wt||No Staining|
|8||73||M||L Maxillary Sinus||wt||wt||wt||5% at 1+|