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Integrated Genomic Classification of Melanocytic Tumors of the Central Nervous System Using Mutation Analysis, Copy Number Alterations, and DNA Methylation Profiling

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Integrated Genomic Classification of Melanocytic Tumors of the Central Nervous System Using Mutation Analysis, Copy Number Alterations, and DNA Methylation Profiling Published OnlineFirst June 11, 2018; DOI: 10.1158/1078-0432.CCR-18-0763 Precision Medicine and Imaging Clinical Cancer Research Integrated Genomic Classification of Melanocytic Tumors of the Central Nervous System Using Mutation Analysis, Copy Number Alterations, and DNA Methylation Profiling Klaus G. Griewank1,2, Christian Koelsche3, Johannes A.P. van de Nes4, Daniel Schrimpf3, Marco Gessi5,6, Inga Moller€ 1, Antje Sucker1, Richard A. Scolyer7,8,9, Michael E. Buckland8,10, Rajmohan Murali11, Torsten Pietsch5, Andreas von Deimling3, and Dirk Schadendorf1 Abstract Purpose: In the central nervous system, distinguishing Results: Combining mutation, copy-number, and DNA- primary leptomeningeal melanocytic tumors from melanoma methylation profiles clearly distinguished cutaneous melanoma metastases and predicting their biological behavior solely metastases from other melanocytic tumors. Primary leptome- using histopathologic criteria may be challenging. We aimed ningeal melanocytic tumors, uveal melanomas, and blue to assess the diagnostic and prognostic value of integrated nevus–like melanoma showed common DNA-methylation, molecular analysis. copy-number alteration, and gene mutation signatures. Notably, Experimental Design: Targeted next-generation sequenc- tumors demonstrating chromosome 3 monosomy and BAP1 ing, array-based genome-wide methylation analysis, and BAP1 alterations formed a homogeneous subset within this group. IHC were performed on the largest cohort of central nervous Conclusions: Integrated molecular profiling aids in distin- system melanocytic tumors analyzed to date, including 47 guishing primary from metastatic melanocytic tumors of the primary tumors of the central nervous system, 16 uveal mel- central nervous system. Primary leptomeningeal melanocytic anomas, 13 cutaneous melanoma metastases, and 2 blue tumors, uveal melanoma, and blue nevus–like melanoma nevus–like melanomas. Gene mutation, DNA-methylation, share molecular similarity with chromosome 3 and BAP1 and copy-number profiles were correlated with clinicopatho- alterations, markers of poor prognosis. Clin Cancer Res; 24(18); logic features. 4494–504. Ó2018 AACR. Introduction cytes. They are termed primary leptomeningeal melanocytic tumors, (1) and are classified according to histopathologic criteria Melanocytic tumors involving the central nervous system can (2), which include mitotic activity, parenchymal infiltration, and be diagnostically challenging. Melanocytic tumors can arise in the Ki67/MIB1 staining. Applying these criteria, primary leptomenin- central nervous system, however, more common are central geal melanocytic tumors are classified as melanocytomas, inter- nervous system melanoma metastases. Correct classification of mediate-grade melanocytomas, and primary leptomeningeal melanocytic tumors of the central nervous system is important for melanomas, referring to benign, atypical/borderline, and malig- prediction of their likely clinical behavior and selecting appro- nant tumors, respectively. However, histopathologic classification priate treatment. of primary leptomeningeal melanocytic tumors is not always The majority of primary melanocytic tumors of the central straightforward. For example, in some primary leptomeningeal nervous system presumably arise from leptomeningeal melano- melanocytic tumors, histopathologic criteria overlap and do not 1Department of Dermatology, University Hospital Essen, West German Cancer Note: Supplementary data for this article are available at Clinical Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Research Online (http://clincancerres.aacrjournals.org/). Germany. 2Dermatopathologie bei Mainz, Nieder-Olm, Germany. 3Department of K.G. Griewank, C. Koelsche, A. von Deimling, and D. Schadendorf contributed Neuropathology, Ruprecht-Karls-University Heidelberg, and Clinical Cooperation equally to this article. Unit Neuropathology, and DKTK, DKFZ, Heidelberg, Germany. 4Institute of Pathology, Ruhr University Bochum, Bochum, Germany. 5Institute of Neuropa- Corresponding Authors: Klaus G. Griewank, University Hospital Essen, thology, University of Bonn Medical Center, Bonn, Germany. 6Division of Histo- Hufelandstrasse 55, Essen 45147, Germany. Phone: 49 201 72385947; pathology, Fondazione Policlinico Universitario "A.Gemelli", Universita Cattolica Fax: 49 201 7235416; Orchid: 0000-0003-3899-9449; E-mail: del Sacro Cuore, Roma, Italy. 7Tissue Pathology and Diagnostic Oncology, Royal [email protected]; and Christian Koelsche, Ruprecht-Karls- Prince Alfred Hospital, Camperdown, NSW, Australia. 8The University of Sydney, University Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Camperdown, NSW, Australia. 9Melanoma Institute Australia, The University of Germany. E-mail: [email protected] Sydney, North Sydney, NSW, Australia. 10Department of Neuropathology, Royal doi: 10.1158/1078-0432.CCR-18-0763 Prince Alfred Hospital, Camperdown, NSW, Australia. 11Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Ó2018 American Association for Cancer Research. 4494 Clin Cancer Res; 24(18) September 15, 2018 Downloaded from clincancerres.aacrjournals.org on October 6, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 11, 2018; DOI: 10.1158/1078-0432.CCR-18-0763 Genetic Analysis of CNS Melanocytic Tumors Each tumor was obtained from a unique patient. In all primary Translational Relevance leptomeningeal melanocytic tumors, a primary melanoma of Melanocytic tumors involving the central nervous system other site, including a uveal melanoma, had been excluded can be diagnostically challenging; in particular, distinguishing (clinical history, imaging, and frequently fundoscopy). The sam- primary leptomeningeal melanocytic tumors and central ner- ples were retrieved from the Institute of Neuropathology and the vous system metastases from cutaneous melanomas may be Department of Dermatology, Essen, Germany, the Department of difficult. We demonstrate that these entities can be distin- Neuropathology, Heidelberg, Germany, the Institute of Neuro- guished based on gene mutation, copy number, and DNA pathology Bonn, Germany, as well as the Melanoma Institute methylation profiles. Additionally, primary leptomeningeal Australia, Sydney, Australia. Some of these tumors have been melanocytic tumors demonstrated copy number, methyla- previously reported (8, 9, 11, 12, 26), but these reports did not tion, and mutation profiles similar to those of uveal melano- include the detailed genetic analyses reported herein. Tumor mas and blue nevus–like melanoma. Monosomy of chromo- slides were reviewed by at least two experienced histopatho- some 3 and BAP1 alterations, markers of poor prognosis in logists (C. Koelsche, J.A.P. van de Nes, M. Gessi, T. Pietsch, uveal melanoma, were also identified in primary leptomenin- K.G. Griewank, R.A. Scolyer, A. von Deimling, or M.E. Buckland). geal melanocytic tumors. In summary, we find that applying The study was performed in accordance with the guidelines genetic analysis in addition to histopathologic examination set forth by the ethics committee of the University of Heidelberg has the potential to improve diagnostic and prognostic eval- and Duisburg-Essen under the IRB protocol numbers 180073 and uation of melanocytic tumors of the central nervous system. 16-6951-BO, respectively. We believe that genetic profiling should become a routine component of the analysis of melanocytic tumors of the Histopathology and IHC central nervous system. Histopathologic examination was performed on routinely stained hematoxylin and eosin slides. Primary leptomeningeal tumors were diagnosed based on criteria described by Brat and colleagues (2). Well-differentiated primary leptomeningeal tumors with no or very low mitotic activity (0–1mitosesper permit ready classification. Others show aggressive biological 10 high-power fields), devoid of central nervous system paren- behavior despite lacking obvious high-grade histopathologic chymal infiltration, and Ki67/MIB1 index 2% were diag- features. nosed as melanocytomas (n ¼ 19). Tumors characterized by Primary leptomeningeal melanocytic tumors and uveal mel- increased mitotic activity (Ki67/MIB1 index 1%–4%) and/or anomas share a similar gene mutation profile (3–9). They microscopic central nervous system parenchymal invasion, frequently harbor mutually exclusive activating hot-spot muta- but not sufficiently anaplastic to warrant the designation of tions in either GNAQ, GNA11, PLCB4,orCYSLTR2 (3–9). melanoma were diagnosed as intermediate-grade melanocy- Additional mutations can also be found in EIF1AX, SF3B1, tomas (n ¼ 22). Tumors demonstrating higher mitotic activity and BAP1, which are also generally detected in a mutually and anaplasia were diagnosed as primary leptomeningeal exclusive pattern (10–12). melanomas (n ¼ 4). Two tumors diagnosed as retrobulbar Cutaneous melanomas consistently demonstrate a very high melanomas were also included in the primary leptomeningeal mutational load and a characteristic UV-exposure mutation sig- melanoma group. nature (13–16). A genetic classification into four groups based on In most cases, IHC was performed on a Ventana Benchmark mutations activating the MAP kinase pathway has been proposed: XT Autostainer using the following markers: S-100 (1:5,000, BRAF-mutated, RAS-mutated, NF1-mutated, or triple wild-type Dako; Z0311); Melan-A (1:100, Dako; M7196); HMB-45 (15, 16). Furthermore, TERT promoter mutations are highly
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