title: Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles.
abstract: BACKGROUND
  Craniopharyngiomas (CP) are rare epithelial tumors of the sellar region. Two subtypes, adamantinomatous (adaCP) and papillary CP (papCP), were previously identified based on histomorphological and epidemiological aspects. Recent data indicates that both variants are defined by specific genetic alterations, and influenced by distinct molecular pathways and particular origins. The fact that CP is an uncommon tumor entity renders studies on large cohorts difficult and exceptional. In order to achieve further insights distinguishing CP variants, we conducted whole genome methylation (450 k array) and microarray-based gene expression studies in addition to CTNNB1 and BRAF mutation analysis using a comprehensive cohort of 80 adaCP and 35 papCP.
  
  
  RESULTS
  BRAF V600E mutations were solely found in the papCP subgroup and were not detectable in adaCP samples. In contrast, CTNNB1 mutations were exclusively detected in adaCP. The methylome fingerprints assigned DNA specimens to entity-specific groups (papCP (n = 18); adaCP (n = 25)) matching perfectly with histology-based diagnosis, suggesting that they represent truly distinct biological entities. However, we were not able to detect within the adaCP group (including 11 pediatric and 14 adult cases) a significant difference in methylation signature by age. Integrative comparison of the papCP with the adaCP group based on differential gene expression and methylation revealed a distinct upregulation of Wnt- and SHH signaling pathway genes in adaCP.
  
  
  CONCLUSIONS
  AdaCP and papCP thus represent distinct tumor subtypes that harbor mutually exclusive gene mutations and methylation patterns, further reflected in differences in gene expression. This study demonstrates that DNA methylation analyses are an additional method to classify CP into subtypes, and implicates a role of epigenetic mechanisms in the genesis of the respective CP variants. Detection of tumor-specific signaling pathway activation enables the possibility of target-oriented intervention.
authors.affiliation: Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany. annett.hoelsken@uk-erlangen.de.
authors.forename: Annett
authors.initials: A
authors.lastname: Hölsken
authors.affiliation: German Cancer Consortium (DKTK) and Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Sill
authors.affiliation: Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Merkle
authors.affiliation: Department of Neuropathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Leonille
authors.initials: L
authors.lastname: Schweizer
authors.affiliation: Institute of Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: Department of Neurosurgery, University Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Flitsch
authors.affiliation: Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fahlbusch
authors.affiliation: Institute of Pediatrics, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Metzler
authors.affiliation: German Cancer Consortium (DKTK) and Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: German Cancer Consortium (DKTK) and Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Department of Neuropathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Department of Neuropathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: German Cancer Consortium (DKTK) and Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Buslei
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003397:Craniopharyngioma / Q000145:classification / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf