Objective: Evidence shows that the switch/sucrose nonfermenting chromatin remodeling complex plays a critical role in DNA repair, cancer progression and dedifferentiation. BRG1 is one of its key catalytic subunits. While the loss of BRG1 expression by immunocytochemistry has been identified in a subset of malignancies arising in various sites with undifferentiated/rhabdoid morphology and poor prognosis, the underlying basis for its loss is unclear. Methods: A retrospective search was conducted in our cytopathology archive for undifferentiated malignant tumors with rhabdoid phenotype and BRG1 loss. Clinical information was obtained from electronic medical records. Next-generation sequencing was performed following macro-dissection of paraffin-embedded cellblock tissue. Results: Three cases were identified; all presented with widely metastatic disease with no previously diagnosed primary malignancy, and subsequently died within 6 months of initial presentation. Cytologically, the aspirates showed dyshesive and undifferentiated cells with rhabdoid features. Extensive immunocytochemical workup demonstrated immunoreactivity with vimentin only and could not establish a specific lineage. BRG1 expression was absent, while INI1 expression was retained. Two cases harbored deleterious mutations in BRG1/SMARCA4. Pathogenic mutations in TP53 were identified in all tumors. Conclusions: BRG1 deficiency reflects underlying mutation in SMARCA4 gene in some but not all cases, suggesting that additional mechanisms may be causing BRG1 silencing. Pathogenic mutations in TP53 in all tumors are consistent with their highly aggressive nature. Recognizing the cytomorphology of this group of neoplasms and confirming their BRG1-deficient status by immunocytochemistry not only has prognostic implications, but may also impart potentially therapeutic value in the near future.

1.
Witkowski
L
,
Carrot-Zhang
J
,
Albrecht
S
,
Fahiminiya
S
,
Hamel
N
,
Tomiak
E
, et al
Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type
.
Nat Genet
.
2014
May
;
46
(
5
):
438
43
.
[PubMed]
1061-4036
2.
Judkins
AR
,
Mauger
J
,
Ht
A
,
Rorke
LB
,
Biegel
JA
.
Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms
.
Am J Surg Pathol
.
2004
May
;
28
(
5
):
644
50
.
[PubMed]
0147-5185
3.
Strehl
JD
,
Wachter
DL
,
Fiedler
J
,
Heimerl
E
,
Beckmann
MW
,
Hartmann
A
, et al
Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant
.
Ann Diagn Pathol
.
2015
Aug
;
19
(
4
):
198
202
.
[PubMed]
1092-9134
4.
Agaimy
A
,
Daum
O
,
Märkl
B
,
Lichtmannegger
I
,
Michal
M
,
Hartmann
A
.
SWI/SNF Complex-deficient Undifferentiated/Rhabdoid Carcinomas of the Gastrointestinal Tract: A Series of 13 Cases Highlighting Mutually Exclusive Loss of SMARCA4 and SMARCA2 and Frequent Co-inactivation of SMARCB1 and SMARCA2
.
Am J Surg Pathol
.
2016
Apr
;
40
(
4
):
544
53
.
[PubMed]
0147-5185
5.
Matsubara
D
,
Kishaba
Y
,
Ishikawa
S
,
Sakatani
T
,
Oguni
S
,
Tamura
T
, et al
Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features
.
Cancer Sci
.
2013
Feb
;
104
(
2
):
266
73
.
[PubMed]
1347-9032
6.
Yoshimoto
T
,
Matsubara
D
,
Nakano
T
,
Tamura
T
,
Endo
S
,
Sugiyama
Y
, et al
Frequent loss of the expression of multiple subunits of the SWI/SNF complex in large cell carcinoma and pleomorphic carcinoma of the lung
.
Pathol Int
.
2015
Nov
;
65
(
11
):
595
602
.
[PubMed]
1320-5463
7.
Le Loarer
F
,
Watson
S
,
Pierron
G
,
de Montpreville
VT
,
Ballet
S
,
Firmin
N
, et al
SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas
.
Nat Genet
.
2015
Oct
;
47
(
10
):
1200
5
.
[PubMed]
1061-4036
8.
Sauter
JL
,
Graham
RP
,
Larsen
BT
,
Jenkins
SM
,
Roden
AC
,
Boland
JM
.
SMARCA4-deficient thoracic sarcoma: a distinctive clinicopathological entity with undifferentiated rhabdoid morphology and aggressive behavior.
Modern Pathology.
2017
: Epublication ahead of print.
9.
Ramos
P
,
Karnezis
AN
,
Craig
DW
,
Sekulic
A
,
Russell
ML
,
Hendricks
WP
, et al
Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4
.
Nat Genet
.
2014
May
;
46
(
5
):
427
9
.
[PubMed]
1061-4036
10.
Marquez-Vilendrer
SB
,
Thompson
K
,
Lu
L
,
Reisman
D
.
Mechanism of BRG1 silencing in primary cancers
.
Oncotarget
.
2016
Aug
;
7
(
35
):
56153
69
.
[PubMed]
1949-2553
11.
Crothers
BA
,
Tench
WD
,
Schwartz
MR
,
Bentz
JS
,
Moriarty
AT
,
Clayton
AC
, et al
Guidelines for the reporting of nongynecologic cytopathology specimens
.
Arch Pathol Lab Med
.
2009
Nov
;
133
(
11
):
1743
56
.
[PubMed]
1543-2165
12.
Ananthanarayanan
V
,
Tretiakova
M
,
Husain
AN
,
Krausz
T
,
Antic
T
.
Carbonic anhydrase IX (CAIX) does not differentiate between benign and malignant mesothelium
.
Am J Clin Pathol
.
2014
Jul
;
142
(
1
):
82
7
.
[PubMed]
0002-9173
13.
Kadri
S
,
Long
BC
,
Mujacic
I
,
Zhen
CJ
,
Wurst
MN
,
Sharma
S
, et al
Clinical Validation of a Next-Generation Sequencing Genomic Oncology Panel via Cross-Platform Benchmarking against Established Amplicon Sequencing Assays
.
J Mol Diagn
.
2017
Jan
;
19
(
1
):
43
56
.
[PubMed]
1525-1578
14.
Kadoch
C
,
Hargreaves
DC
,
Hodges
C
,
Elias
L
,
Ho
L
,
Ranish
J
, et al
Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy
.
Nat Genet
.
2013
Jun
;
45
(
6
):
592
601
.
[PubMed]
1061-4036
15.
Strobeck
MW
,
Reisman
DN
,
Gunawardena
RW
,
Betz
BL
,
Angus
SP
,
Knudsen
KE
, et al
Compensation of BRG-1 function by Brm: insight into the role of the core SWI-SNF subunits in retinoblastoma tumor suppressor signaling
.
J Biol Chem
.
2002
Feb
;
277
(
7
):
4782
9
.
[PubMed]
0021-9258
16.
Biegel
JA
,
Zhou
JY
,
Rorke
LB
,
Stenstrom
C
,
Wainwright
LM
,
Fogelgren
B
.
Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors
.
Cancer Res
.
1999
Jan
;
59
(
1
):
74
9
.
[PubMed]
0008-5472
17.
Guidi
CJ
,
Sands
AT
,
Zambrowicz
BP
,
Turner
TK
,
Demers
DA
,
Webster
W
, et al
Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice
.
Mol Cell Biol
.
2001
May
;
21
(
10
):
3598
603
.
[PubMed]
0270-7306
18.
Roberts
CW
,
Galusha
SA
,
McMenamin
ME
,
Fletcher
CD
,
Orkin
SH
.
Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice
.
Proc Natl Acad Sci USA
.
2000
Dec
;
97
(
25
):
13796
800
.
[PubMed]
0027-8424
19.
Hornick
JL
,
Dal Cin
P
,
Fletcher
CD
.
Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma
.
Am J Surg Pathol
.
2009
Apr
;
33
(
4
):
542
50
.
[PubMed]
0147-5185
20.
Calderaro
J
,
Moroch
J
,
Pierron
G
,
Pedeutour
F
,
Grison
C
,
Maillé
P
, et al
SMARCB1/INI1 inactivation in renal medullary carcinoma
.
Histopathology
.
2012
Sep
;
61
(
3
):
428
35
.
[PubMed]
0309-0167
21.
Jo
VY
,
Fletcher
CD
.
Epithelioid malignant peripheral nerve sheath tumor: clinicopathologic analysis of 63 cases
.
Am J Surg Pathol
.
2015
May
;
39
(
5
):
673
82
.
[PubMed]
0147-5185
22.
Agaimy
A
,
Rau
TT
,
Hartmann
A
,
Stoehr
R
.
SMARCB1 (INI1)-negative rhabdoid carcinomas of the gastrointestinal tract: clinicopathologic and molecular study of a highly aggressive variant with literature review
.
Am J Surg Pathol
.
2014
Jul
;
38
(
7
):
910
20
.
[PubMed]
0147-5185
23.
Agaimy
A
,
Haller
F
,
Frohnauer
J
,
Schaefer
IM
,
Ströbel
P
,
Hartmann
A
, et al
Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes
.
Mod Pathol
.
2015
Feb
;
28
(
2
):
248
60
.
[PubMed]
0893-3952
24.
Rodriguez-Nieto
S
,
Cañada
A
,
Pros
E
,
Pinto
AI
,
Torres-Lanzas
J
,
Lopez-Rios
F
, et al
Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors
.
Hum Mutat
.
2011
Feb
;
32
(
2
):
E1999
2017
.
[PubMed]
1059-7794
25.
Marquez
SB
,
Thompson
KW
,
Lu
L
,
Reisman
D
.
Beyond Mutations: Additional Mechanisms and Implications of SWI/SNF Complex Inactivation
.
Front Oncol
.
2015
Feb
;
4
:
372
.
[PubMed]
2234-943X
26.
Agulnik
M
,
Tannir
NM
,
Pressey
JG
,
Gounder
MM
,
Cote
GM
,
Roche
M
, et al
A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adult subjects with INI1-negative tumors or relapsed/refractory synovial sarcoma
.
J Clin Oncol
.
2016
;
34
15_suppl
:
TPS11071
11071
. 0732-183X
27.
Hoffman
GR
,
Rahal
R
,
Buxton
F
,
Xiang
K
,
McAllister
G
,
Frias
E
, et al
Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers
.
Proc Natl Acad Sci USA
.
2014
Feb
;
111
(
8
):
3128
33
.
[PubMed]
0027-8424
28.
Tagal
V
,
Wei
S
,
Zhang
W
,
Brekken
RA
,
Posner
BA
,
Peyton
M
, et al
SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers
.
Nat Commun
.
2017
Jan
;
8
:
14098
.
[PubMed]
2041-1723
29.
Gramling
S
,
Rogers
C
,
Liu
G
,
Reisman
D
.
Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy
.
Oncogene
.
2011
Jul
;
30
(
29
):
3289
94
.
[PubMed]
0950-9232
30.
Schiaffino-Ortega
S
,
Balinas
C
,
Cuadros
M
,
Medina
PP
.
SWI/SNF proteins as targets in cancer therapy
.
J Hematol Oncol
.
2014
Nov
;
7
(
1
):
81
.
[PubMed]
1756-8722
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