title: Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma.
abstract: Mutations of the NF2 gene on chromosome 22q are thought to initiate tumorigenesis in nearly 50% of meningiomas, and 22q deletion is the earliest and most frequent large-scale chromosomal abnormality observed in these tumors. In aggressive meningiomas, 22q deletions are generally accompanied by the presence of large-scale segmental abnormalities involving other chromosomes, but the reasons for this association are unknown. We find that large-scale chromosomal alterations accumulate during meningioma progression primarily in tumors harboring 22q deletions, suggesting 22q-associated chromosomal instability. Here we show frequent codeletion of the DNA repair and tumor suppressor gene, CHEK2, in combination with NF2 on chromosome 22q in a majority of aggressive meningiomas. In addition, tumor-specific splicing of CHEK2 in meningioma leads to decreased functional Chk2 protein expression. We show that enforced Chk2 knockdown in meningioma cells decreases DNA repair. Furthermore, Chk2 depletion increases centrosome amplification, thereby promoting chromosomal instability. Taken together, these data indicate that alternative splicing and frequent codeletion of CHEK2 and NF2 contribute to the genomic instability and associated development of aggressive biologic behavior in meningiomas.
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Yang
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.forename: Sydney S
authors.initials: SS
authors.lastname: Song
authors.forename: Nihal
authors.initials: N
authors.lastname: Shrinath
authors.forename: Richard
authors.initials: R
authors.lastname: Park
authors.forename: Michel
authors.initials: M
authors.lastname: Kalamarides
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.forename: Peter M
authors.initials: PM
authors.lastname: Black
authors.forename: Rona S
authors.initials: RS
authors.lastname: Carroll
authors.forename: Mark D
authors.initials: MD
authors.lastname: Johnson
mesh_terms: D017398:Alternative Splicing; D015153:Blotting, Western; D064447:Checkpoint Kinase 2; D043171:Chromosomal Instability / Q000235:genetics*; D018450:Disease Progression; D017353:Gene Deletion; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000473:pathology; D008579:Meningioma / Q000235:genetics* / Q000473:pathology; D060787:Neoplasm Grading; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases