Abstract
Introduction: The interaction of K27M mutation in histone H3 (H3K27M mutation) with polycomb repressive complex 2 (PRC2) is facilitated by the enhancer of zeste homolog 2 (EZH2). Subsequently, this interaction leads to the global reduction level of H3K27me3. We analyzed the EZH2 expression level in H3K27M mutation-positive tumors and revealed the association of high EZH2 expression with poor survival. Methods: Our study included 12 patients, with an age range of 6–56 years and treated between 2007 and 2016. All patients underwent MRI study for nonenhanced T1, T2, diffusion, gadolinium-enhanced T1-weighted imaging, and fluid-attenuated inversion recovery (FLAIR). Immunohistochemical staining was performed against H3K27M, H3K27me3, EZH2, EED, mutant isocitrate dehydrogenase 1 (IDH1), α-thalassemia X-linked intellectual disability (ATRX), p53, O6-methylguanine-DNA methyltransferase (MGMT), and Ki-67 antibodies. Results: All patients were negative for IDH1R132H and H3K27me3, but H3K27M-positive. Staining against EZH2 was negative in all histological features of grade II cases (3/12) and positive in grade III and IV cases; EZH2 positivity is associated with poor prognosis (p = 0.0082). EZH2 positivity was not associated with EED positivity. Retained ATRX staining was found mostly in grade III and IV cases (6/12). P53 was predominantly positive in cases of astrocytoma and glioblastoma (8/12). The labeling index of Ki-67 was 1.2–31.4% for grade II and III histological features and 11.2–24.8% for grade IV. Conclusion: We suggest that the expression of EZH2 is not associated with the PRC2 pathway and increases in patients with H3K27M-mutant diffuse midline glioma and a poor prognosis. Further studies are necessary to understand the mechanism involved.
References
1.
Cutter
AR
, Hayes
JJ
(2015
) A brief review of nucleosome structure.
FEBS Lett 7;589(20PartA):2914–22. 2.
Bannister
AJ
, Kouzarides
T
. Regulation of chromatin by histone modifications
. Cell Res
. 2011
Mar
;21
(3
):381
–95
.
[PubMed]
1001-06023.
Margueron
R
, Reinberg
D
(2011
) The Polycomb complex PRC2 and its mark in life.
Nature 19;469:343. 4.
Simon
JA
, Kingston
RE
(2013
) Occupying Chromatin: polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic and staying put.
Mol Cell 7;49(5):808–24. 5.
Wu
G
, Broniscer
A
, McEachron
TA
, Lu
C
, Paugh
BS
, Becksfort
J
, et al.; St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project
. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas
. Nat Genet
. 2012
Jan
;44
(3
):251
–3
.
[PubMed]
1061-40366.
Wu
G
, Diaz
AK
, Paugh
BS
, Rankin
SL
, Ju
B
, Li
Y
, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma
. Nat Genet
. 2014
May
;46
(5
):444
–50
.
[PubMed]
1061-40367.
Lewis
PW
, Müller
MM
, Koletsky
MS
, Cordero
F
, Lin
S
, Banaszynski
LA
, et al. (2013
) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.
Science 17;340(6134):857–61. 8.
Michalak
EM
, Visvader
JE
(2016
) Dysregulation of histone methyltransferases in breast cancer – opportunities for new targeted therapies? Mol Oncol 1;10(10):1497–515.9.
Jia
N
, Li
Q
, Tao
X
, Wang
J
, Hua
K
, Feng
W
. Enhancer of zeste homolog 2 is involved in the proliferation of endometrial carcinoma
. Oncol Lett
. 2014
Nov
;8
(5
):2049
–54
.
[PubMed]
1792-107410.
Ngollo
M
, Lebert
A
, Dagdemir
A
, Judes
G
, Karsli-Ceppioglu
S
, Daures
M
, et al. (2014
) The association between Histone 3 Lysine 27 trimethylation (H3K27me3) and prostate cancer: relationship with clinicopathological parameters. BMC Cancer 23;14:994.11.
Dimou
A
, Dincman
T
, Evanno
E
, Gemmill
R
, Roche
J
, Drabkin
H
(2017
) Epigenetics during EMT in lung cancer: EZH2 as a potential therapeutic target. Cancer Treat Res Commun Jun 1;12.12.
13.
Louis
DN
, Ohgaki
H
, Wiestler
O
, Cavenee
WK
, Ellison
DW
, Figarella-Branger
D
, et al. (2016
) WHO classification of tumours of the central nervous system revised 4th. Lyon: Internationa Agency for Research on Cancer (IARC).14.
Venneti
S
, Santi
M
, Felicella
MM
, Yarilin
D
, Phillips
JJ
, Sullivan
LM
, et al. (2014
) A sensitive and specific histopathologic prognostic marker for K27M mutant pediatric glioblastomas. Acta Neuropathol (Berl) 1;128(5):743–53.15.
Bender
S
, Tang
Y
, Lindroth
AM
, Hovestadt
V
, Jones
DTW
, Kool
M
, et al. (2013
) Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 11;24(5):660–72.16.
Solomon
DA
, Wood
MD
, Tihan
T
, Bollen
AW
, Gupta
N
, Phillips
JJJ
, et al. (2016
) Diffuse Midline Gliomas with Histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 1;26(5):569–80.17.
Morita
S
, Nitta
M
, Muragaki
Y
, Komori
T
, Masui
K
, Maruyama
T
, et al. (2017
) Brainstem pilocytic astrocytoma with H3 K27M mutation: case report. J Neurosurg. http://thejns.org/action/showCitFormats?doi=10.3171%2F2017.4.JNS162443. Accessed 16 Jan 2018.18.
Pagès
M
, Beccaria
K
, Boddaert
N
, Saffroy
R
, Besnard
A
, Castel
D
, et al. (2018
) Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma. Brain Pathol 1;28(1):103–11.19.
Joyon
N
, Tauziède-Espariat
A
, Alentorn
A
, Giry
M
, Castel
D
, Capelle
L
, et al. (2017
) K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway. Neuropathol Appl Neurobiol 1;43(3):271–6.20.
Venneti
S
, Garimella
MT
, Sullivan
LM
, Martinez
D
, Huse
JT
, Heguy
A
, et al. (2013
) Evaluation of Histone 3 Lysine 27 Trimethylation (H3K27me3) and Enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol 1;23(5):558–64.21.
Capper
D
, Weissert
S
, Balss
J
, Habel
A
, Meyer
J
, Jäger
D
, et al. Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors
. Brain Pathol
. 2010
Jan
;20
(1
):245
–54
.
[PubMed]
1015-630522.
Wiestler
B
, Capper
D
, Holland-Letz
T
, Korshunov
A
, Deimling
A
von
, Pfister
SM
, et al. (2013
) ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis.
Acta Neuropathol (Berl) 1;126(3):443–51. 23.
Takami
H
, Yoshida
A
, Fukushima
S
, Arita
H
, Matsushita
Y
, Nakamura
T
, et al. Revisiting TP53 mutations and immunohistochemistry: a Comparative study in 157 diffuse gliomas
. Brain Pathol
. 2015
May
;25
(3
):256
–65
.
[PubMed]
1015-630524.
Skjulsvik
AJ
, Mørk
JN
, Torp
MO
, Torp
SH
. Ki-67/MIB-1 immunostaining in a cohort of human gliomas
. Int J Clin Exp Pathol
. 2014
Dec
;7
(12
):8905
–10
.
[PubMed]
1936-262525.
Füllgrabe
J
, Kavanagh
E
, Joseph
B
(2011
) Histone onco-modifications.
Oncogene 25;30:3391. 26.
Vastenhouw
NL
, Schier
AF
(2012
) Bivalent histone modifications in early embryogenesis.
Nucl Gene Expr 1;24(3):374–86. 27.
Justin
N
, Zhang
Y
, Tarricone
C
, Martin
SR
, Chen
S
, Underwood
E
, et al. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nat Commun. 2016
28;7:1131628.
Chan
K-M
, Fang
D
, Gan
H
, Hashizume
R
, Yu
C
, Schroeder
M
, et al. (2013
) The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev 1;27(9):985–90.29.
Reddington
JP
, Perricone
SM
, Nestor
CE
, Reichmann
J
, Youngson
NA
, Suzuki
M
, et al. (2013
) Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes.
Genome Biol 25;14:R25. 30.
Schwartzentruber
J
, Korshunov
A
, Liu
XY
, Jones
DT
, Pfaff
E
, Jacob
K
, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
. Nature
. 2012
Jan
;482
(7384
):226
–31
.
[PubMed]
0028-083631.
Comet
I
, Riising
EM
, Leblanc
B
, Helin
K
(2016
) Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer 23;16:803.32.
Hock
H.
A complex Polycomb issue: the two faces of EZH2 in cancer
(2012
) Genes Dev. 15;26(8):751–5. 33.
Gall Trošelj
K
, Novak Kujundzic
R
, Ugarkovic
D
(2016
) Polycomb repressive complex’s evolutionary conserved function: the role of EZH2 status and cellular background.
Clin Epigenetics 27;8:55. 34.
Simon
C
, Chagraoui
J
, Krosl
J
, Gendron
P
, Wilhelm
B
, Lemieux
S
, et al. (2012
) A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 1;26(7):651–6.35.
Muto
T
, Sashida
G
, Oshima
M
, Wendt
GR
, Mochizuki-Kashio
M
, Nagata
Y
, et al. (2013
) Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J Exp Med 18;210(12):2627–39.36.
Crea
F
, Hurt
EM
, Farrar
WL
(2010
) Clinical significance of Polycomb gene expression in brain tumors.
Mol Cancer 30;9:265. 37.
Orzan
F
, Pellegatta
S
, Poliani
PL
, Pisati
F
, Caldera
V
, Menghi
F
, et al. (2011
) Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol 1;37(4):381–94.38.
Zhang
Y
, Yu
X
, Chen
L
, Zhang
Z
, Feng
S
, Zhang
Y
, et al. (2016
) EZH2 overexpression is associated with poor prognosis in patients with glioma.
Oncotarget 21;8(1):565–73.39.
Zhang
J
, Chen
L
, Han
L
, Shi
Z
, Zhang
J
, Pu
P
, et al. (2015
) EZH2 is a negative prognostic factor and exhibits pro-oncogenic activity in glioblastoma.
Cancer Lett 28;356(2):929–36. 40.
Mohammad
F
, Weissmann
S
, Leblanc
B
, Pandey
DP
, Højfeldt
JW
, Comet
I
, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas
. Nat Med
. 2017
Apr
;23
(4
):483
–92
.
[PubMed]
1078-895641.
Piunti
A
, Hashizume
R
, Morgan
MA
, Bartom
ET
, Horbinski
CM
, Marshall
SA
, et al. Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas
. Nat Med
. 2017
Apr
;23
(4
):493
–500
.
[PubMed]
1078-895642.
Creasy
CL
. Untangling the role of mutant histone H3 in diffuse intrinsic pontine glioma
. Nat Med
. 2017
Apr
;23
(4
):413
–4
.
[PubMed]
1078-895643.
Khuong-Quang
D-A
, Buczkowicz
P
, Rakopoulos
P
, Liu
X-Y
, Fontebasso
AM
, Bouffet
E
, et al. (2012
) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol (Berl) 1;124(3):439–47.44.
Castel
D
, Philippe
C
, Calmon
R
, Le Dret
L
, Truffaux
N
, Boddaert
N
, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes
. Acta Neuropathol
. 2015
Dec
;130
(6
):815
–27
.
[PubMed]
0001-632245.
Capper
D
, Mittelbronn
M
, Meyermann
R
, Schittenhelm
J
. Pitfalls in the assessment of MGMT expression and in its correlation with survival in diffuse astrocytomas: proposal of a feasible immunohistochemical approach
. Acta Neuropathol
. 2008
Feb
;115
(2
):249
–59
.
[PubMed]
0001-6322© 2019 S. Karger AG, Basel
2019
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