SMARCA4/BRG1

Stains
SMARCA4/BRG1

Authors: Susan M. Armstrong, M.D., Ph.D., Brendan C. Dickson, M.D., M.Sc.

Editorial Board Member: Brendan C. Dickson, M.D., M.Sc.

Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 5 March 2019

Minor changes: 31 August 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: SMARCA4/BRG1

Page views in 2019: 1,480

Page views in 2020 to date: 2,618

Table of Contents

Cite this page: Armstrong SM, Dickson BC. SMARCA4/BRG1 . PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsSMARCA4BRG1.html. Accessed September 20th, 2020.

Definition / general

SMARCA4 (SWI / SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) encodes a protein involved in chromatin remodeling, which is important for regulating the binding of transcription factors to DNA (also known as BRG1 and hSNF2β, amongst others; NCBI Gene ID: 6597)
As an evolutionarily conserved regulator of many transcription factors, it is important in mammalian tissue development and differentiation (Trends Genet 2007;23:403, Mol Cell Biol 2011;31:2618)

Essential features

Loss of SMARCA4 characterizes several distinct neoplasms, including: small cell carcinoma of the ovary hypercalcemic type (Am J Surg Pathol 2016;40:395), SMARCA4 deficient undifferentiated uterine sarcoma (Mod Pathol 2018;31:1442) and SMARCA4 deficient thoracic sarcoma (Nat Genet 2015;47:1200)
While SMARCA4 is considered a tumor suppressor gene, both loss of protein expression as well as protein upregulation have been associated with neoplasia (Sci Rep 2018;8:2043, Cancer Res 2003;63:560)
It is frequently mutated in a variety of cancer cell lines (Hum Mutat 2008;29:617)

Pathophysiology

A component of the SWI / SNF complex, which is involved in chromatin remodeling and thus the regulation of gene expression (Nature 1993;366:170, Cell Res 2011;21:396)
Plays a role in tumor suppression directly as well as through interaction with other key cancer related proteins (BRCA1, Rb, p53, beta-catenin, etc.) (Cell 2000;102:257, Cell 1994;79:119, J Biol Chem 2002;277:22330, EMBO J 2001;20:4935)
May also play roles in DNA repair or cell cycle control (EMBO J 2010;29:1434, Cell Death Dis 2017;8:e2607)

Clinical features

Heterozygous germline SMARCA4 mutations are associated with an autosomal dominant condition known as rhabdoid tumor predisposition syndrome-2 (OMIM #613325)
A subset of patients with Coffin-Siris syndrome, specifically CSS4, a congenital malformation syndrome, bear a heterozygous germline SMARCA4 mutation (OMIM #614609)

Interpretation

SMARCA4 has a nuclear pattern of immunohistochemical expression (Nature 1993;366:170); SMARCA4 deficient neoplasms have complete loss of staining amongst tumor cells with retained expression by nonneoplastic tissues (e.g., blood vessels, lymphocytes)
There is no established cutoff for determining high versus low expression; staining of the surrounding normal tissue has been used as a median value relative to which SMARCA4 expression may be considered increased or decreased (Int J Oncol 2013;42:403)

Uses by pathologists

To aid in the diagnosis of ovarian small cell carcinoma, hypercalcemic type (ovarian rhabdoid tumor) (Nat Genet 2014;46:424, J Pathol 2014;233:209, Am J Surg Pathol 2015;39:1197, Am J Surg Pathol 2016;40:395)
To aid in the diagnosis of SMARCA4 deficient thoracic sarcoma (Nat Genet 2015;47:1200, Mod Pathol 2017;30:1422, Am J Surg Pathol 2018 Nov 16 [Epub ahead of print])
To aid in the diagnosis of SMARCA4 deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus; Mod Pathol 2018;31:1442)
To confirm the diagnosis of malignant rhabdoid tumors or epithelioid sarcoma in which SMARCB1 / INI1 expression is intact (Am J Hum Genet 2010;86:279, Am J Surg Pathol 2018;42:312)

Prognostic factors

Concomitant loss of SMARCA4 and BRM in non small cell lung cancer is associated with worse prognosis (Cancer Res 2003;63:560)
Loss of expression of SMARCA4 is associated with improved prognosis in clear cell renal cell carcinoma (Oncotarget 2017;8:37423)
Increased SMARCA4 expression is associated with worse prognosis in patients with breast invasive ductal carcinoma (Anticancer Res 2016;36:4873), hepatocellular carcinoma and clear cell renal cell carcinoma (Sci Rep 2018;8:2043)

Microscopic (histologic) images

Contributed by Rose Chami, M.D. and Catherine Chung, M.D.

Ovarian small cell carcinoma, hypercalcemic type

Positive staining - normal

Most normal tissues contain intact nuclear SMARCA4 expression

Negative staining - normal

Not applicable

Positive staining - disease

Most tumors typically contain intact nuclear expression
Increased expression has been reported in melanoma (Br J Dermatol 2010;163:502), gastric cancer (Pathobiology 2001;69:315), glioma (J Cancer Res Clin Oncol 2012;138:991), prostate adenocarcinoma (Prostate 2007;67:203) and colorectal cancer (Br J Cancer 2011;104:146)

Negative staining - disease

Small cell carcinoma of the ovary, hypercalcemic type (ovarian rhabdoid tumor) (Nat Genet 2014;46:424, J Pathol 2014;233:209, Am J Surg Pathol 2015;39:1197,Am J Surg Pathol 2016;40:395)
SMARCA4 deficient thoracic sarcoma (Nat Genet 2015;47:1200, Mod Pathol 2017;30:1422, Am J Surg Pathol 2018 Nov 16 [Epub ahead of print])
SMARCA4 deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus) (Mod Pathol 2018;31:1442)
Subsets of rhabdoid tumor (Am J Hum Genet 2010;86:279) and epithelioid sarcoma (Am J Surg Pathol 2018;42:312)
Endometrial adenocarcinoma, poorly / undifferentiated (Ann Diagn Pathol 2015;19:198, Histopathology 2017;70:359)
A subset of non small cell lung cancer (Hum Mutat 2011;32:E1999)
A subset of pancreatic intraductal papillary mucinous neoplasms (Hum Pathol 2012;43:585)

Molecular / cytogenetics description

In small cell carcinoma of the ovary, whole exome sequencing demonstrated
- Frequent loss of heterozygosity at chromosome 19, the location of SMARCA4
- Some cases with point mutations or small indels (insertion or deletion of bases) (Oncotarget 2016;7:1732)
- A subset of patients have underlying germline SMARCA4 mutations (Nat Genet 2014;46:427, Nat Genet 2014;46:438)
In SMARCA4 deficient thoracic sarcoma, mRNA sequencing showed the presence of SMARCA4 gene mutations (nonsense, frameshift, missense and splice site) (Nat Genet 2015;47:1200)

Board review style question #1

Colorectal adenocarcinoma
Melanoma
Small cell carcinoma of the lung
Small cell carcinoma of the ovary, hypercalcemic type

Board review answer #1

D. Small cell carcinoma of the ovary, hypercalcemic type

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