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


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.

DOI: 10.1038/ng.3399

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@article{Loarer2015SMARCA4ID, title={SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas}, author={François Le Loarer and Sarah Watson and Gaelle Pierron and Vincent Thomas de Montpr{\'e}ville and Stelly Ballet and Nelly Firmin and Aur{\'e}lie Auguste and Daniel Pissaloux and Sandrine Boyault and Sandrine Paindavoine and Pierre Joseph Dechelotte and Benjamin Besse and Jean Michel Vignaud and Marie Brevet and {\'E}lie Fadel and Wilfrid Richer and Isabelle Treilleux and Julien Masliah-Planchon and Mojgan Devouassoux-Shisheboran and G erard Zalcman and Yves Allory and Franck Bourdeaut and Françoise Thivolet-B{\'e}jui and Dominique Ranch{\`e}re-Vince and Nicolas Girard and Sylvie Lantu{\'e}joul and Françoise B Galateau-Sall{\'e} and Jean Michel Coindre and Alexandra F Leary and Olivier Delattre and Jean-Yves Blay and Franck Tirode}, journal={Nature Genetics}, year={2015}, volume={47}, pages={1200-1205} }