title: CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways.
abstract: CNS germinomas represent a unique germ cell tumor entity characterized by undifferentiated tumor cells and a high response rate to current treatment protocols. Limited information is available on their underlying genomic, epigenetic and biological alterations. We performed a genome-wide analysis of genomic copy number alterations in 49 CNS germinomas by molecular inversion profiling. In addition, CpG dinucleotide methylation was studied by immunohistochemistry for methylated cytosine residues. Mutational analysis was performed by resequencing of candidate genes including KIT and RAS family members. Ras/Erk and Akt pathway activation was analyzed by immunostaining with antibodies against phospho-Erk, phosho-Akt, phospho-mTOR and phospho-S6. All germinomas coexpressed Oct4 and Kit but showed an extensive global DNA demethylation compared to other tumors and normal tissues. Molecular inversion profiling showed predominant genomic instability in all tumors with a high frequency of regional gains and losses including high level gene amplifications. Activating mutations of KIT exons 11, 13, and 17 as well as a case with genomic KIT amplification and activating mutations or amplifications of RAS gene family members including KRAS, NRAS and RRAS2 indicated mutational activation of crucial signaling pathways. Co-activation of Ras/Erk and Akt pathways was present in 83% of germinomas. These data suggest that CNS germinoma cells display a demethylated nuclear DNA similar to primordial germ cells in early development. This finding has a striking coincidence with extensive genomic instability. In addition, mutational activation of Kit-, Ras/Raf/Erk- and Akt- pathways indicate the biological importance of these pathways and their components as potential targets for therapy.
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Simone Laura
authors.initials: SL
authors.lastname: Schulte
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Steiger
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Dorota
authors.initials: D
authors.lastname: Denkhaus
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Dörner
authors.affiliation: Department of Pediatric Hematology/Oncology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Calaminus
authors.affiliation: Kiel Paediatric Tumor Registry, Department of Paediatric Pathology, University Hospital of Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Leuschner
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D043171:Chromosomal Instability; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D018237:Germinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011494:Protein Kinases; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins
keywords: genomics; germinoma; hypomethylation; Ras; c-Kit