SMARCA4/BRG1-Deficient Non-Small Cell Lung Carcinomas: A Case Series and Review of the Literature.

Abstract

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.

• Authors: Aruna Nambirajan, Varsha Singh, Nishu Bhardwaj, Saurabh Mittal, Sunil Kumar, Deepali Jain
• Journal: Archives of pathology & laboratory medicine (Arch Pathol Lab Med) Vol. 145 Issue 1 Pg. 90-98 (01 01 2021) ISSN: 1543-2165 [Electronic] United States
• PMID: 33367658 (Publication Type: Journal Article, Review)
• Copyright: © 2021 College of American Pathologists.

Chemical References

• MAS1 protein, human
• Nuclear Proteins
• Proto-Oncogene Mas
• Transcription Factors
• SMARCA4 protein, human
• DNA Helicases

Topics

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism, pathology)
• DNA Helicases (deficiency, genetics)
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Male
• Middle Aged
• Nuclear Proteins (deficiency, genetics)
• Proto-Oncogene Mas
• Retrospective Studies
• Transcription Factors (deficiency, genetics)