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 complexes1,2. 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)3,4,5, SMARCB1-inactivated malignant rhabdoid tumors6 (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations7). 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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Acknowledgements
We thank the following pathologists who provided archival material: C. Bazille, F. Beltjens, P.P. Bringuier, J. Calderaro, L. Chalabreysse, M.C. Charpentier, M.C. Château, A. Clemenson, S. Collardeau-Frachon, S. Croce, A. Croue, F. Dauchat, A.V. Decouvelaere, P. Dorfmuller, S. Duquenne, F. Forest, S. Garcia, M.R. Ghigna, I. Goubin Versini, A. Jouvet, E. Longchamp, P. Michenet, F. Mishellany, A. Moreau, H. Perrochia, B. PetitJean, J.M. Picquenot, P. Roger, V. Secques, I. Serre, I. Soubeyran, J.P. Terrier, A. Traverse-Glehen, I. Valo and L. Zemoura. We also thank the following clinicians who provided follow-up information: D. Arpin, F. Barlesi, J.O. Bay, T. Berghmans, P. Cassier, L. Cany, D. Cupissol, L. Diaz, P. Dumont, P. Fevrier, D. Fric, E. Huchot, N. Isambert, S. Labrune, V. Laurence, D. Moro-sibilot, M. Pays, I. Ray Coquard, O. Regnard, C. Rizzo, S. Salas and P.A. Thomas. We are grateful to J. Auclair, M. Carrere, S. Chabaud, A. Colombe, V. Dapremont, V. Haddad, M. Jean-Denis, F. Lorcy, N. Mesli, J.P. Michot, D. Postoly, G. Schummer, A. Shumikhin, V. Velascoa and Q. Wang. INSERM U830 is supported by the Institut National de la Santé et de la Recherche Médicale, the Institut Curie, the Ligue National Contre Le Cancer (Equipe Labellisée), the Institut National du Cancer and la Direction Générale de l'Offre de Soins (INCa-DGOS_5716), the European PROVABES (ERA-649 NET TRANSCAN JTC-2011), ASSET (FP7-HEALTH-2010-259348) and the Euro Ewing Consortium (HEALTH-F2-2013-602856) projects. W.R. is supported by the SiRIC Institut Curie program. U830 is also indebted to the Société Française des Cancers de l'Enfant, Enfants et Santé, Courir pour Mathieu, Dans les Pas du Géant, La Course de l'Espoir du Mont Valérien, Au Nom d'Andréa, Association Abigaël, Association Marabout de Ficelle, Les Bagouz à Manon, Les Amis de Claire and Association Adam. S.W. is supported by a grant from the Fondation Nuovo-Soldati. High-throughput sequencing was performed by the next-generation sequencing platform of Institut Curie, supported by grants ANR-10-EQPX-03 and ANR-10-INBS-09-08 from the Agence Nationale de la Recherche (Investissements d'Avenir) and by Canceropôle Ile-de-France. INSERM U1052 is supported by grants from LYRIC (DGOS-INCa 4664), NetSARC (INCa), RREPS (INCa), LabEx DEvweCAN (ANR-10-LABX-0061), Eurosarc (FP7-278742) and Ligue de l'Ain Contre le Cancer.
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F.L.L. initiated and designed the study, collected samples, performed experiments, analyzed the data and wrote the manuscript. S.W. initiated the study, analyzed the data and helped write the manuscript. G.P. and S. Ballet provided, prepared and sequenced biological samples of unclassified sarcoma. V.T.d.M., J.M.V., F.T.-B., D.R.-V., S.L. and F.G.-S. provided samples and were the reference senior pathologists. P.J.D., M.B., M.D.-S. and J.M.C. provided samples. N.F., E.F., B.B., G.Z. and N.G. recruited patients and provided clinical information. I.T. supervised all immunohistochemical experiments. D.P., S. Boyault and S.P. performed and analyzed OncoScan experiments. W.R., J.M.-P. and F.B. provided, prepared and sequenced biological samples of MRT and epithelioid sarcoma. Y.A. provided biological samples of RMC. A.A. and A.L. provided, prepared and sequenced biological samples of SCCOHT. O.D. gave biological and genetic guidance, provided infrastructure and helped write the manuscript. J.Y.B. initiated, designed and supervised the study and helped write the manuscript. F.T. initiated, designed, coordinated and supervised the study, performed the bioinformatics analyses, analyzed the data and wrote the manuscript.
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Supplementary Text and Figures
Supplementary Figures 1–24, Supplementary Tables 1, 3–11 and 14, and Supplementary Note. (PDF 8262 kb)
Supplementary Table 2
Variation identified by RNA-seq. (XLSX 113 kb)
Supplementary Table 12
Genes differentially expressed between SMARCA4-DTS and lung carcinoma (SMARCA4mt). (XLSX 127 kb)
Supplementary Table 13
Genes differentially expressed between SMARCA4-DTS and US(T). (XLSX 55 kb)
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Le Loarer, F., Watson, S., Pierron, G. et al. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat Genet 47, 1200–1205 (2015). https://doi.org/10.1038/ng.3399
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DOI: https://doi.org/10.1038/ng.3399
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