Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins

Research output: Contribution to journalArticle

Leomar Y Ballester, Zain Boghani, David S Baskin, Gavin W Britz, Randall Olsen, Gregory N Fuller, Suzanne Z Powell, Matthew D Cykowski

Astrocytes with multiple micronuclei ("Creutzfeldt cells") in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high-grade glioma vs tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood. Studies have proposed that micronuclei in Creutzfeldt cells are a consequence of DNA damage, or may be susceptible to DNA damage and chromothripsis, but their biology in the context of glioblastoma remains unclear. Based on a challenging index case of GBM with mild hypercellularity, Creutzfeldt astrocytes, and granular mitoses on biopsy, we searched our archives for additional cases with similar histopathologic features. We identified 13 cases, reviewed their clinico-radiologic and pathologic features, and examined them for recurrent genetic alterations via NGS (9 cases) and for evidence of DNA damage by immunohistochemistry for DNA repair and chromatin remodeling proteins. We found that Creutzfeldt cell-rich GBMs were IDH-wildtype with no recurring genetic alterations. To test our hypothesis that micronuclei demonstrate loss of DNA repair or chromatin remodeling proteins, we examined the expression of various proteins (MDM2, p53, MLH1, MSH2, PMS2, MSH6, ATRX, INI1, SATB2, Ki67, pHH3) in Creutzfeldt cell rich-GBM. There was intact expression of DNA repair and chromatin remodeling proteins, with accumulation of p53 and reduced MDM2 expression within micronuclei. In contrast, granular mitoses showed pHH3 expression, confirming these cells are undergoing mitotic division, with no accumulation of p53 and reduced expression of DNA repair proteins. Our results emphasize that Creutzfeldt cells are part of the morphologic spectrum of IDH-wildtype glioblastoma. We did not find a role for DNA damage in the generation of Creutzfeldt cells, as both DNA repair and chromatin remodeling protein expression was retained in these cells.

Original languageEnglish (US)
Pages (from-to)1012-1019
Number of pages8
JournalBrain Pathology
Volume28
Issue number6
Early online dateMar 6 2018
DOIs
StatePublished - Nov 1 2018

PMID: 29509313

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Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins. / Ballester, Leomar Y; Boghani, Zain; Baskin, David S; Britz, Gavin W; Olsen, Randall; Fuller, Gregory N; Powell, Suzanne Z; Cykowski, Matthew D.

In: Brain Pathology, Vol. 28, No. 6, 01.11.2018, p. 1012-1019.

Research output: Contribution to journalArticle

Harvard

Ballester, LY, Boghani, Z, Baskin, DS, Britz, GW, Olsen, R, Fuller, GN, Powell, SZ & Cykowski, MD 2018, 'Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins' Brain Pathology, vol. 28, no. 6, pp. 1012-1019. https://doi.org/10.1111/bpa.12604

APA

Ballester, L. Y., Boghani, Z., Baskin, D. S., Britz, G. W., Olsen, R., Fuller, G. N., ... Cykowski, M. D. (2018). Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins. Brain Pathology, 28(6), 1012-1019. https://doi.org/10.1111/bpa.12604

Vancouver

Ballester LY, Boghani Z, Baskin DS, Britz GW, Olsen R, Fuller GN et al. Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins. Brain Pathology. 2018 Nov 1;28(6):1012-1019. https://doi.org/10.1111/bpa.12604

Author

Ballester, Leomar Y ; Boghani, Zain ; Baskin, David S ; Britz, Gavin W ; Olsen, Randall ; Fuller, Gregory N ; Powell, Suzanne Z ; Cykowski, Matthew D. / Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins. In: Brain Pathology. 2018 ; Vol. 28, No. 6. pp. 1012-1019.

BibTeX

@article{ac5d026500aa4dc39f45eb8a01a3c175,
title = "Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins",
abstract = "Astrocytes with multiple micronuclei ({"}Creutzfeldt cells{"}) in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high-grade glioma vs tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood. Studies have proposed that micronuclei in Creutzfeldt cells are a consequence of DNA damage, or may be susceptible to DNA damage and chromothripsis, but their biology in the context of glioblastoma remains unclear. Based on a challenging index case of GBM with mild hypercellularity, Creutzfeldt astrocytes, and granular mitoses on biopsy, we searched our archives for additional cases with similar histopathologic features. We identified 13 cases, reviewed their clinico-radiologic and pathologic features, and examined them for recurrent genetic alterations via NGS (9 cases) and for evidence of DNA damage by immunohistochemistry for DNA repair and chromatin remodeling proteins. We found that Creutzfeldt cell-rich GBMs were IDH-wildtype with no recurring genetic alterations. To test our hypothesis that micronuclei demonstrate loss of DNA repair or chromatin remodeling proteins, we examined the expression of various proteins (MDM2, p53, MLH1, MSH2, PMS2, MSH6, ATRX, INI1, SATB2, Ki67, pHH3) in Creutzfeldt cell rich-GBM. There was intact expression of DNA repair and chromatin remodeling proteins, with accumulation of p53 and reduced MDM2 expression within micronuclei. In contrast, granular mitoses showed pHH3 expression, confirming these cells are undergoing mitotic division, with no accumulation of p53 and reduced expression of DNA repair proteins. Our results emphasize that Creutzfeldt cells are part of the morphologic spectrum of IDH-wildtype glioblastoma. We did not find a role for DNA damage in the generation of Creutzfeldt cells, as both DNA repair and chromatin remodeling protein expression was retained in these cells.",
keywords = "chromothripsis, Creutzfeldt astrocytes, glioblastoma, granular mitosis, micronuclei, mismatch repair protein",
author = "Ballester, {Leomar Y} and Zain Boghani and Baskin, {David S} and Britz, {Gavin W} and Randall Olsen and Fuller, {Gregory N} and Powell, {Suzanne Z} and Cykowski, {Matthew D}",
note = "{\circledC} 2018 International Society of Neuropathology.",
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language = "English (US)",
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pages = "1012--1019",
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RIS

TY - JOUR

T1 - Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins

AU - Ballester, Leomar Y

AU - Boghani, Zain

AU - Baskin, David S

AU - Britz, Gavin W

AU - Olsen, Randall

AU - Fuller, Gregory N

AU - Powell, Suzanne Z

AU - Cykowski, Matthew D

N1 - © 2018 International Society of Neuropathology.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Astrocytes with multiple micronuclei ("Creutzfeldt cells") in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high-grade glioma vs tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood. Studies have proposed that micronuclei in Creutzfeldt cells are a consequence of DNA damage, or may be susceptible to DNA damage and chromothripsis, but their biology in the context of glioblastoma remains unclear. Based on a challenging index case of GBM with mild hypercellularity, Creutzfeldt astrocytes, and granular mitoses on biopsy, we searched our archives for additional cases with similar histopathologic features. We identified 13 cases, reviewed their clinico-radiologic and pathologic features, and examined them for recurrent genetic alterations via NGS (9 cases) and for evidence of DNA damage by immunohistochemistry for DNA repair and chromatin remodeling proteins. We found that Creutzfeldt cell-rich GBMs were IDH-wildtype with no recurring genetic alterations. To test our hypothesis that micronuclei demonstrate loss of DNA repair or chromatin remodeling proteins, we examined the expression of various proteins (MDM2, p53, MLH1, MSH2, PMS2, MSH6, ATRX, INI1, SATB2, Ki67, pHH3) in Creutzfeldt cell rich-GBM. There was intact expression of DNA repair and chromatin remodeling proteins, with accumulation of p53 and reduced MDM2 expression within micronuclei. In contrast, granular mitoses showed pHH3 expression, confirming these cells are undergoing mitotic division, with no accumulation of p53 and reduced expression of DNA repair proteins. Our results emphasize that Creutzfeldt cells are part of the morphologic spectrum of IDH-wildtype glioblastoma. We did not find a role for DNA damage in the generation of Creutzfeldt cells, as both DNA repair and chromatin remodeling protein expression was retained in these cells.

AB - Astrocytes with multiple micronuclei ("Creutzfeldt cells") in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high-grade glioma vs tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood. Studies have proposed that micronuclei in Creutzfeldt cells are a consequence of DNA damage, or may be susceptible to DNA damage and chromothripsis, but their biology in the context of glioblastoma remains unclear. Based on a challenging index case of GBM with mild hypercellularity, Creutzfeldt astrocytes, and granular mitoses on biopsy, we searched our archives for additional cases with similar histopathologic features. We identified 13 cases, reviewed their clinico-radiologic and pathologic features, and examined them for recurrent genetic alterations via NGS (9 cases) and for evidence of DNA damage by immunohistochemistry for DNA repair and chromatin remodeling proteins. We found that Creutzfeldt cell-rich GBMs were IDH-wildtype with no recurring genetic alterations. To test our hypothesis that micronuclei demonstrate loss of DNA repair or chromatin remodeling proteins, we examined the expression of various proteins (MDM2, p53, MLH1, MSH2, PMS2, MSH6, ATRX, INI1, SATB2, Ki67, pHH3) in Creutzfeldt cell rich-GBM. There was intact expression of DNA repair and chromatin remodeling proteins, with accumulation of p53 and reduced MDM2 expression within micronuclei. In contrast, granular mitoses showed pHH3 expression, confirming these cells are undergoing mitotic division, with no accumulation of p53 and reduced expression of DNA repair proteins. Our results emphasize that Creutzfeldt cells are part of the morphologic spectrum of IDH-wildtype glioblastoma. We did not find a role for DNA damage in the generation of Creutzfeldt cells, as both DNA repair and chromatin remodeling protein expression was retained in these cells.

KW - chromothripsis

KW - Creutzfeldt astrocytes

KW - glioblastoma

KW - granular mitosis

KW - micronuclei

KW - mismatch repair protein

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U2 - 10.1111/bpa.12604

DO - 10.1111/bpa.12604

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JO - Brain Pathology

T2 - Brain Pathology

JF - Brain Pathology

SN - 1015-6305

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ID: 39585550