SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas

Abstract

While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models

“…In this study, we report data to support further the existence of a class of rhabdoid-like tumors that not only represent a mesenchymal stem cell-like group of cancers that have misregulated SWI/SNF function (characterized by SWI/SNF loss of function mutations) but that are also dependent on PRC2 activity. This specific tumor class also shares clinical and histopathological features and has been found to carry a BAF-deficient sarcoma gene signature that is represented by developmental and embryonic stem cell programs (37). It is important to note that loss of SWI/SNF components alone does not predict sensitivity to EZH2 inhibition.…”

“…An area of high interest is therefore to test the contribution of the tumor microenvironment in ARID1A-mutated in vivo models upon tazemetostat treatment. The cancer cell-of-origin appears to be a critical codeterminant of dependence on EZH2 activity; transcriptome analysis performed on a select number of SWI/SNF altered primary tumors revealed that SMARCA4-or INI1-deficient rhabdoid-like tumors clustered together and away from SMARCA4-deficient lung tumors, a more epithelial and more differentiated type of tumor (37). In addition, data from our CRISPR pooled screen show that knocking out SMARCA4 in a SMARCA2 low-expressing cell line (and vice versa) does not sensitize the cells to tazemetostat treatment further supporting the importance of the cell of origin.…”

“…To characterize further these SCCOHT cell lines, we performed transcriptome analysis of all ovarian cell lines within the CCLE dataset using the developmental and embryonic stem cell program signature that is characteristic of BAF-deficient sarcomas (ref. 37; Fig. 1D).…”

Cytologic Features of SMARCA4-Deficient Thoracic Sarcoma: A Case Report and Comparison with Other SWI/SNF Complex-Deficient Tumors

“…Recently, a distinct subset of intrathoracic undifferentiated tumors, termed SMARCA4-deficient thoracic sarcomas (SMARCA4-DTSs), was described by Le Loarer et al [1]. These tumors are characterized by the inactivation of SMARCA4 , a gene encoding an ATPase subunit of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes.…”

SMARCA4-deficient Sinonasal Carcinoma

“…Among the SWI/SNF proteins, SMARCA4 loss has been recently identified as the main or sole alteration driving small cell carcinoma of the ovary, hypercalcemic type [10]. Other SMARCA4-driven neoplasms include a rare subset of highly aggressive thoracic malignancies [11] as well as a subset of non-small cell lung cancer (NSCLC) [12] and others. To our knowledge, SMARCA4 loss has not been demonstrated to date in sinonasal tract carcinoma.…”