title: Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations.
abstract: Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.
authors: Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
authors: David E
authors: DE
authors: Reuss
authors: Rosario M
authors: RM
authors: Piro
authors: David T W
authors: DT
authors: Jones
authors: Matthias
authors: M
authors: Simon
authors: Ralf
authors: R
authors: Ketter
authors: Marcel
authors: M
authors: Kool
authors: Albert
authors: A
authors: Becker
authors: Felix
authors: F
authors: Sahm
authors: Stefan
authors: S
authors: Pusch
authors: Jochen
authors: J
authors: Meyer
authors: Christian
authors: C
authors: Hagenlocher
authors: Leonille
authors: L
authors: Schweizer
authors: David
authors: D
authors: Capper
authors: Phillipp
authors: P
authors: Kickingereder
authors: Jana
authors: J
authors: Mucha
authors: Christian
authors: C
authors: Koelsche
authors: Natalie
authors: N
authors: Jäger
authors: Thomas
authors: T
authors: Santarius
authors: Patrick S
authors: PS
authors: Tarpey
authors: Philip J
authors: PJ
authors: Stephens
authors: P
authors: P
authors: Andrew Futreal
authors: Ruth
authors: R
authors: Wellenreuther
authors: Jürgen
authors: J
authors: Kraus
authors: Doris
authors: D
authors: Lenartz
authors: Christel
authors: C
authors: Herold-Mende
authors: Christian
authors: C
authors: Hartmann
authors: Christian
authors: C
authors: Mawrin
authors: Nathalia
authors: N
authors: Giese
authors: Roland
authors: R
authors: Eils
authors: V Peter
authors: VP
authors: Collins
authors: Rainer
authors: R
authors: König
authors: Otmar D
authors: OD
authors: Wiestler
authors: Stefan M
authors: SM
authors: Pfister
authors: Andreas
authors: A
authors: von Deimling
mesh_terms: D004252:DNA Mutational Analysis; D023281:Genomics; D005973:Glutamine / Q000235:genetics; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008239:Lysine / Q000235:genetics; D008577:Meningeal Neoplasms / Q000235:genetics*; D008579:Meningioma / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics*
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C486460:TRAF7 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D005973:Glutamine; D008239:Lysine