Stains & CD markers
SMARCA4/BRG1
Copyright: 2002-2023, PathologyOutlines.com, Inc.
PubMed Search: SMARCA4/BRG1
SMARCA4/BRG1
Editor-in-Chief: Debra L. Zynger, M.D.
Last author update: 5 March 2019
Last staff update: 7 December 2022 (update in progress)
Copyright: 2002-2023, PathologyOutlines.com, Inc.
PubMed Search: SMARCA4/BRG1
Table of Contents
Definition / general | Essential features | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Positive staining - normal | Negative staining - normal | Positive staining - disease | Negative staining - disease | Molecular / cytogenetics description | Board review style question #1 | Board review style answer #1Cite this page: Armstrong SM, Dickson BC. SMARCA4/BRG1 . PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsSMARCA4BRG1.html. Accessed February 8th, 2023.
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
- Which of the following is associated with loss of SMARCA4 expression?
- Colorectal adenocarcinoma
- Melanoma
- Small cell carcinoma of the lung
- Small cell carcinoma of the ovary, hypercalcemic type
Board review style answer #1
