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

Abstract

Purpose: In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria may be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis.Experimental Design: Targeted next-generation sequencing, array-based genome-wide methylation analysis, and BAP1 IHC were performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, including 47 primary tumors of the central nervous system, 16 uveal melanomas, 13 cutaneous melanoma metastases, and 2 blue nevus-like melanomas. Gene mutation, DNA-methylation, and copy-number profiles were correlated with clinicopathologic features.Results: Combining mutation, copy-number, and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas, and blue nevus-like melanoma showed common DNA-methylation, copy-number alteration, and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group.Conclusions: Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma, and blue nevus-like melanoma share molecular similarity with chromosome 3 and BAP1 alterations, markers of poor prognosis. Clin Cancer Res; 24(18); 4494-504. ©2018 AACR.

• Authors: Klaus G Griewank, Christian Koelsche, Johannes A P van de Nes, Daniel Schrimpf, Marco Gessi, Inga Möller, Antje Sucker, Richard A Scolyer, Michael E Buckland, Rajmohan Murali, Torsten Pietsch, Andreas von Deimling, Dirk Schadendorf
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 18 Pg. 4494-4504 (Sep 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29891723 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• BAP1 protein, human
• Tumor Suppressor Proteins
• Ubiquitin Thiolesterase

Topics

• Adult
• Aged
• Aged, 80 and over
• Central Nervous System Neoplasms (classification, genetics, pathology)
• Chromosomes, Human, Pair 3 (genetics)
• DNA Copy Number Variations (genetics)
• DNA Methylation (genetics)
• DNA Mutational Analysis
• Female
• Genomics
• Humans
• Male
• Melanoma (classification, genetics, pathology)
• Middle Aged
• Mutation (genetics)
• Neoplasm Metastasis
• Nevus, Blue (classification, genetics, pathology)
• Sequence Analysis, DNA
• Skin Neoplasms (classification, genetics, pathology)
• Tumor Suppressor Proteins (genetics)
• Ubiquitin Thiolesterase (genetics)
• Uveal Neoplasms (classification, genetics, pathology)
• Melanoma, Cutaneous Malignant