Recent updates in thoracic SMARCA4-deficient undifferentiated tumor
Aruna Nambirajan1, Deepali Jain1
1Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Abstract:
Germline inactivating mutations in SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene encoding for BRG1 (Brahma related gene-1) are the molecular drivers in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) and in malignant rhabdoid tumors (MRT) that occur in the context of rhabdoid tumor predisposition syndrome-type 2. Somatic SMARCA4 mutations and/or loss of BRG1 have been identified in a variety of adult-onset epithelial and mesenchymal neoplasms. Among thoracic tumors, these include subsets of smoking-related non-small cell lung carcinoma (NSCLC) and a relatively rare, newly recognised tumor entity: thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Less than 100 cases of SMARCA4-UT have been reported to date. They present as large compressive and infiltrative mediastinal, lung and/or pleural masses in middle-aged male smokers. They are undifferentiated tumors composed of sheets of small/epithelioid and/or rhabdoid tumor cells variably expressing epithelial markers and consistently showing loss of BRG1 and the closely related protein, Brahma (BRM). Frequent expression of stem cell markers (SOX2, CD34, SALL4) is noted. Despite gene expression profiles similar to MRTs and SCCOHT, they show striking genomic overlap with SMARCA4-mutant NSCLC with frequent TP53, STK11, KEAP1, and KRAS mutations, high tumor mutation burden (TMB), and presence of smoking related molecular signatures in tumor cells. SMARCA4-UT show uniformly poor survival and are irresponsive to conventional therapies. Immunotherapy responses are variable but promising, although PDL1 expression appears to be of poor predictive value. Drugs exploiting genetic and epigenetic mechanisms of SMARCA4 antagonism hold promise for future targeted therapies.
Insights
Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive cancers linked to SMARCA4 gene mutations. These tumors show poor survival and resistance to standard treatments, but immunotherapy and targeted therapies show promise.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Germline mutations in the SMARCA4 gene are key drivers in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and malignant rhabdoid tumors (MRT).
- Somatic SMARCA4 mutations and BRG1 loss are found in various adult cancers, including subsets of non-small cell lung carcinoma (NSCLC).
- A rare thoracic tumor, SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), has been recently recognized, with fewer than 100 cases reported.
Purpose of the Study:
- To characterize the clinical, pathological, and molecular features of thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT).
- To investigate the genomic landscape and potential therapeutic strategies for SMARCA4-UT.
Main Methods:
- Analysis of clinical presentations, histopathology, and immunohistochemical profiles of SMARCA4-UT cases.
- Genomic profiling including mutation analysis (TP53, STK11, KEAP1, KRAS), tumor mutation burden (TMB) assessment, and identification of smoking-related molecular signatures.
- Review of treatment responses, including conventional therapies, immunotherapy (PDL1 expression), and potential targeted agents.
Main Results:
- SMARCA4-UT present as large, infiltrative mediastinal, lung, or pleural masses in middle-aged male smokers.
- Tumors are undifferentiated, composed of cells with rhabdoid features, consistently showing loss of BRG1 and BRM, with frequent expression of stem cell markers (SOX2, CD34, SALL4).
- Genomically, SMARCA4-UT overlap with SMARCA4-mutant NSCLC, featuring frequent TP53, STK11, KEAP1, KRAS mutations, high TMB, and smoking signatures. They exhibit poor survival and resistance to conventional therapies, with variable immunotherapy responses.
Conclusions:
- Thoracic SMARCA4-UT are aggressive neoplasms molecularly linked to SMARCA4 inactivation, sharing genomic features with SMARCA4-mutant NSCLC.
- Current treatment strategies are largely ineffective, highlighting the need for novel therapeutic approaches.
- Targeted therapies exploiting SMARCA4 antagonism and potentially immunotherapy represent promising avenues for future treatment of SMARCA4-UT.
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