Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma

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

doi:10.1593/neo.111574

Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma

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

Department of Medical Informatics

Brigham and Women’s Hospital
Harvard University
Institut national de la santé et de la recherche médicale
Université Paris Cité

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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.

Original language	English
Pages (from-to)	20-28
Number of pages	9
Journal	Neoplasia
Volume	14
Issue number	1
DOIs	https://doi.org/10.1593/neo.111574
State	Published - Jan 2012

Bibliographical note

Funding Information:
Address all correspondence to: Mark D. Johnson, MD, PhD, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115. E-mail: mjohnson27@ partners.org 1This work was supported by a grant from the Brain Science Foundation to M.D.J. and R.S.C. and by a National Institutes of Health Director’s New Innovator Award (DP2OD002319) and R01 NS062219 from the National Institute of Neurological Disorders and Stroke to M.D.J. The authors have no conflicts of interest or competing financial interests. Received 11 November 2011; Revised 23 December 2011; Accepted 3 January 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.111574

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1593/neo.111574

Cite this

@article{0cd852e205bc4f8c8daa022bde9f6137,

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.",

author = "Yang, \{Hong Wei\} and Kim, \{Tae Min\} and Song, \{Sydney S.\} and Nihal Shrinath and Richard Park and Michel Kalamarides and Park, \{Peter J.\} and Black, \{Peter M.\} and Carroll, \{Rona S.\} and Johnson, \{Mark D.\}",

note = "Funding Information: Address all correspondence to: Mark D. Johnson, MD, PhD, Department of Neurosurgery, Brigham and Women{\textquoteright}s Hospital, Boston, MA 02115. E-mail: mjohnson27@ partners.org 1This work was supported by a grant from the Brain Science Foundation to M.D.J. and R.S.C. and by a National Institutes of Health Director{\textquoteright}s New Innovator Award (DP2OD002319) and R01 NS062219 from the National Institute of Neurological Disorders and Stroke to M.D.J. The authors have no conflicts of interest or competing financial interests. Received 11 November 2011; Revised 23 December 2011; Accepted 3 January 2012 Copyright {\textcopyright} 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/\$25.00 DOI 10.1593/neo.111574",

year = "2012",

month = jan,

doi = "10.1593/neo.111574",

language = "English",

volume = "14",

pages = "20--28",

journal = "Neoplasia",

issn = "1522-8002",

publisher = "Elsevier Inc.",

number = "1",

}

TY - JOUR

T1 - Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma

AU - Yang, Hong Wei

AU - Kim, Tae Min

AU - Song, Sydney S.

AU - Shrinath, Nihal

AU - Park, Richard

AU - Kalamarides, Michel

AU - Park, Peter J.

AU - Black, Peter M.

AU - Carroll, Rona S.

AU - Johnson, Mark D.

N1 - Funding Information: Address all correspondence to: Mark D. Johnson, MD, PhD, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115. E-mail: mjohnson27@ partners.org 1This work was supported by a grant from the Brain Science Foundation to M.D.J. and R.S.C. and by a National Institutes of Health Director’s New Innovator Award (DP2OD002319) and R01 NS062219 from the National Institute of Neurological Disorders and Stroke to M.D.J. The authors have no conflicts of interest or competing financial interests. Received 11 November 2011; Revised 23 December 2011; Accepted 3 January 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.111574

PY - 2012/1

Y1 - 2012/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84863056301

U2 - 10.1593/neo.111574

DO - 10.1593/neo.111574

M3 - Article

AN - SCOPUS:84863056301

SN - 1522-8002

VL - 14

SP - 20

EP - 28

JO - Neoplasia

JF - Neoplasia

IS - 1

ER -

Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this