Document Detail


Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma.
MedLine Citation:
PMID:  22355270     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Hong Wei Yang; Tae-Min Kim; Sydney S Song; Nihal Shrinath; Richard Park; Michel Kalamarides; Peter J Park; Peter M Black; Rona S Carroll; Mark D Johnson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  14     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-02-22     Completed Date:  2012-06-12     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  20-8     Citation Subset:  IM    
Affiliation:
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Alternative Splicing*
Blotting, Western
Chromosomal Instability / genetics*
Disease Progression
Gene Deletion
Genes, Neurofibromatosis 2*
Humans
Meningeal Neoplasms / genetics*,  pathology
Meningioma / genetics*,  pathology
Neoplasm Grading
Protein-Serine-Threonine Kinases / genetics*
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
DP2OD002319/OD/NIH HHS; R01 NS062219/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
EC 2.7.1.11/checkpoint kinase 2; EC 2.7.11.1/Protein-Serine-Threonine Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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