Recent updates in thoracic SMARCA4-deficient undifferentiated tumor
Aruna Nambirajan1, Deepali Jain1
1Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Seminars in Diagnostic Pathology
|June 20, 2021
Summary
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.
Related Concept Videos
02:07Tumor Progression
6.7K
Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
6.7K
02:23Abnormal Proliferation
4.8K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.8K