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Updated: Nov 24, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
SMARCA4/BRG1-Deficient Non-Small Cell Lung Carcinomas: A Case Series and Review of the Literature
Aruna Nambirajan1, Varsha Singh1, Nishu Bhardwaj1
1From the Departments of Pathology (Nambirajan, Bhardwaj, Jain, Singh), All India Institute of Medical Sciences, New Delhi, India.
Context.—:
Somatic mutations in SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and/or BRG1 (Brahma-related gene 1) loss identifies a subset of non-small cell lung carcinomas (NSCLCs) lacking alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1) genes. Preliminary observations suggest responsiveness to immunotherapy and targeted therapies.
Objective.—:
To study BRG1 loss in NSCLCs and elucidate the clinicopathologic profile of such SMARCA4-deficient NSCLCs.
Design.—:
Non-small cell lung carcinomas diagnosed during 6 years were subject to immunohistochemistry for BRG1 and BRM (Brahma). Tumors with BRG1 loss were stained with antibodies against thyroid transcription factor 1 (TTF-1), p40, cytokeratins, hepatocyte paraffin 1 (Hep Par 1), Sal-like protein 4 (SALL4), CD34, SRY-box 2 (SOX2), chromogranin, synaptophysin, p53, integrase interactor 1, ALK, and ROS1. EGFR mutation testing was performed by polymerase chain reaction-based method.
Results.—:
Among 100 NSCLCs tested, 4 cases (4%) showed BRG1 loss. The histology ranged from solid adenocarcinomas (n = 1) to large cell/poorly differentiated carcinomas (n = 3) with clear cell cytology in 2 cases. All showed loss/reduction of BRM with variable cytokeratin and SALL4 expression, and were negative for TTF-1, p40, Hep Par 1, ALK, ROS1, and EGFR mutations. CD34 and SOX2 were negative in all 4 cases. Isolated BRM loss was common (21%), distributed across all NSCLC subtypes including squamous cell carcinomas and a hepatoid adenocarcinoma.
Conclusions.—:
BRG1 loss occurs in a subset of TTF-1/p40-negative poorly differentiated NSCLCs. Identification and follow-up will clarify the prognosis, diagnostic criteria, and potential for therapeutic personalization.
Insights
SMARCA4-deficient non-small cell lung cancers (NSCLCs) with BRG1 loss are rare, often poorly differentiated, and lack common mutations. Further study is needed to clarify prognosis and therapeutic strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene mutations and/or BRG1 (Brahma-related gene 1) loss define a distinct subset of non-small cell lung carcinomas (NSCLCs).
- These NSCLCs typically lack common driver mutations in EGFR, ALK, and ROS1.
- Preliminary findings suggest potential responsiveness to immunotherapy and targeted therapies.
Purpose of the Study:
- To investigate the clinicopathologic profile of SMARCA4-deficient NSCLCs characterized by BRG1 loss.
- To identify diagnostic markers and understand the characteristics of these tumors.
Main Methods:
- Immunohistochemistry was performed on 100 NSCLCs to assess BRG1 and BRM (Brahma) expression.
- Tumors with BRG1 loss underwent staining for TTF-1, p40, cytokeratins, Hep Par 1, SALL4, CD34, SOX2, chromogranin, synaptophysin, p53, integrase interactor 1, ALK, and ROS1.
- EGFR mutation analysis was conducted using PCR.
Main Results:
- Four cases (4%) of NSCLC exhibited BRG1 loss.
- Histological subtypes included solid adenocarcinoma (n=1) and poorly differentiated/large cell carcinomas (n=3), with two showing clear cell cytology.
- These tumors were negative for TTF-1, p40, Hep Par 1, ALK, ROS1, and EGFR mutations, with variable cytokeratin and SALL4 expression and loss/reduction of BRM.
Conclusions:
- BRG1 loss identifies a subset of poorly differentiated NSCLCs that are negative for TTF-1 and p40.
- Further research is required to establish the prognostic implications, refine diagnostic criteria, and explore personalized therapeutic options for these tumors.
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