Targeted next generation sequencing of mucosal melanomas identifies frequent <i>NF1</i> and <i>RAS</i> mutations

Abstract

// Ioana Cosgarea 1 , Selma Ugurel 1 , Antje Sucker 1 , Elisabeth Livingstone 1 , Lisa Zimmer 1 , Mirjana Ziemer 2 , Jochen Utikal 3 , Peter Mohr 4 , Christiane Pfeiffer 5 , Claudia Pf&ouml;hler 6 , Uwe Hillen 1 , Susanne Horn 1 , Dirk Schadendorf 1 , Klaus G. Griewank 1, * and Alexander Roesch 1, * 1 Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), University of Duisburg-Essen, Duisburg/Essen, Germany 2 Department of Dermatology, Venereology and Allergology, University Hospital Leipzig, Germany 3 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany 4 Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude, Germany 5 Department of Dermatology, Klinikum Augsburg, Augsburg, Germany 6 Department of Dermatology, Saarland University Medical School, Homburg/Saar, Germany * These authors have contributed equally to this work Correspondence to: Klaus G. Griewank, email: klaus.griewank@uk-essen.de Alexander Roesch, email: alexander.roesch@uk-essen.de Keywords: mucosal melanoma, NF1 , RAS , sequencing, melanoma Received: December 28, 2016&emsp;&emsp;&emsp;&emsp; Accepted: February 15, 2017&emsp;&emsp;&emsp;&emsp; Published: March 24, 2017 ABSTRACT Purpose: Mucosal melanoma represents ~1% of all melanomas, frequently having a poor prognosis due to diagnosis at a late stage of disease. Mucosal melanoma differs from cutaneous melanoma not only in terms of poorer clinical outcome but also on the molecular level having e.g. less BRAF and more frequent KIT mutations than cutaneous melanomas. For the majority of mucosal melanomas oncogenic driver mutations remain unknown. Experimental Design and Results: In our study, 75 tumor tissues from patients diagnosed with mucosal melanoma were analyzed, applying a targeted next generation sequencing panel covering 29 known recurrently mutated genes in melanoma. NF1 and RAS mutations were identified as the most frequently mutated genes occurring in 18.3% and 16.9% of samples, respectively. Mutations in BRAF were identified in 8.4% and KIT in 7.0% of tumor samples. Conclusions: Our study identifies NF1 as the most frequently occurring driver mutation in mucosal melanoma. RAS alterations, consisting of NRAS and KRAS mutations, were the second most frequent mutation type. BRAF and KIT mutations were rare with frequencies below 10% each. Our data indicate that in mucosal melanomas RAS / NF1 alterations are frequent, implying a significant pathogenetic role for MAPK and potentially PI3K pathway activation in these tumors.