Melanotic tumors of the nervous system are characterized by distinct mutational, chromosomal and epigenomic profiles

Abstract

Melanotic tumors of the nervous system show overlapping histological characteristics but differ substantially in their biological behavior. In order to achieve a better delineation of such tumors, we performed an in-depth molecular characterization. Eighteen melanocytomas, 12 melanomas, and 14 melanotic and 14 conventional schwannomas (control group) were investigated for methylome patterns (450k array), gene mutations associated with melanotic tumors and copy number variants (CNVs). The methylome fingerprints assigned tumors to entity-specific groups. Methylation groups also showed a substantial overlap with histology-based diagnosis suggesting that they represent true biological entities. On the molecular level, melanotic schwannomas were characterized by a complex karyotype with recurrent monosomy of chromosome 22q and variable whole chromosomal gains and recurrent losses commonly involving chromosomes 1, 17p and 21. Melanocytomas carried GNAQ/11 mutations and presented with CNV involving chromosomes 3 and 6. Melanomas were frequently mutated in the TERT promoter, harbored additional oncogene mutations and showed recurrent chromosomal losses involving chromosomes 9, 10 and 6q, as well as gains of 22q. Together, melanotic nervous system tumors have several distinct mutational and chromosomal alterations and can reliably be distinguished by methylome profiling.

Keywords: 450k; GNA11; GNAQ; TERT promoter; copy number variants; melanocytoma; melanoma; melanotic schwannoma.

Figure 1

Molecular profiling of melanotic nervous system tumors. Heatmap depicting unsupervised hierarchical clustering of methylation levels of the top 6223 most variant probes (SD >0.25) in melanotic tumors of the nervous system. Each row represents a probe; each column represents a sample. The level of DNA methylation (beta value) is represented with a color scale as depicted. Conventional schwannomas served as control group. For each sample (n = 58), associated methylation group, results of oncogene sequencing, selected chromosomal copy number variants (CNVs) and histological diagnosis are indicated. * = partial losses included.

Figure 2

Numerical chromosomal alterations in melanotic nervous system tumors. Chromosomal ideograms summarizing the chromosomal copy number aberrations of 18 melanocytomas (A) and 9 melanotic schwannomas (B) identified by 450k processed data. Green bars indicate areas with copy number gain and red bars indicate areas with copy number loss. A representative copy number plot is given for each tumor type.