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

Francois Le Loarer 1, 2, 3 Sarah Watson 4 Gaëlle Pierron 5 Vincent Thomas de Montpreville 6 Stelly Ballet 5 Nelly Firmin 7 Aurelie A. Auguste 8 Daniel Pissaloux 3 Sandrine Boyault 3 Sandrine Paindavoine 3 Pierre Joseph Dechelotte 9 Benjamin Besse 10, 11 Jean Michel Vignaud 12 Marie Brevet 2 Elie Fadel 11, 6 Wilfrid Richer 4, 13 Isabelle Treilleux 3 Julien Masliah-Planchon 4, 5 Mojgan Devouassoux-Shisheboran 14 Gérard Zalcman 15 Yves Allory 16, 17, 18 Franck Bourdeaut 5 Françoise Thivolet-Béjui 2 Dominique Ranchere-Vince 3 Nicolas Girard 2, 19 Sylvie Lantuejoul 20, 21 Françoise Galateau-Sallé 22, 23 Jean Michel Coindre 24 Alexandra Leary 8, 25 Olivier Delattre 4 Jean Yves Blay 1, 2 Franck Tirode 4 
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.
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Francois Le Loarer, Sarah Watson, Gaëlle Pierron, Vincent Thomas de Montpreville, Stelly Ballet, et al.. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nature Genetics, 2015, 47 (10), pp.1200 - 1205. ⟨10.1038/ng.3399⟩. ⟨hal-01684775⟩



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