Melanotic tumors of the nervous system are characterized by distinct mutational, chromosomal and epigenomic profiles.
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.
Department of Neuropathology, Institute of Pathology, University Medical Center, Heidelberg, Germany; German Cancer Consortium (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Christian
C
Koelsche
Volker
V
Hovestadt
David T W
DT
Jones
David
D
Capper
Dominik
D
Sturm
Felix
F
Sahm
Daniel
D
Schrimpf
Sebastian
S
Adeberg
Katja
K
Böhmer
Christian
C
Hagenlocher
Gunhild
G
Mechtersheimer
Patricia
P
Kohlhof
Helmut
H
Mühleisen
Rudi
R
Beschorner
Christian
C
Hartmann
Anne Kristin
AK
Braczynski
Michel
M
Mittelbronn
Rolf
R
Buslei
Albert
A
Becker
Alexander
A
Grote
Horst
H
Urbach
Ori
O
Staszewski
Marco
M
Prinz
Ekkehard
E
Hewer
Stefan M
SM
Pfister
Andreas
A
von Deimling
David E
DE
Reuss
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics*; D002648:Child; D002869:Chromosome Aberrations; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008545:Melanoma / Q000145:classification / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009442:Neurilemmoma / Q000145:classification / Q000235:genetics*; D055815:Young Adult
450k; GNA11; GNAQ; TERT promoter; copy number variants; melanocytoma; melanoma; melanotic schwannoma