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.
Cancer Research Center of Lyon, INSERM U1052, Lyon, France.|Centre Leon Berard, Department of Pathology, Lyon, France.|Université Claude Bernard Lyon 1, Lyon, France.
Francois
http://orcid.org/0000-0001-8582-9819
F
Le Loarer
Genetics and Biology of Cancer Unit, Institut Curie Research Center, Paris Sciences et Lettres Research University, Paris, France.|INSERM U830, Institut Curie Research Center, Paris, France.
Sarah
S
Watson
Institut Curie Hospital Group, Unité de Génétique Somatique, Paris, France.
Gaelle
G
Pierron
Centre Chirurgical Marie Lannelongue, Department of Pathology, Le Plessis Robinson, France.
Vincent Thomas
VT
de Montpreville
Institut Curie Hospital Group, Unité de Génétique Somatique, Paris, France.
Stelly
S
Ballet
Institut de Cancerologie de Montpellier, Department of Oncology, Montpellier, France.
Nelly
N
Firmin
Gustave Roussy, INSERM U981, Villejuif, France.
Aurelie
A
Auguste
Centre Leon Berard, Department of Pathology, Lyon, France.
Daniel
D
Pissaloux
Centre Leon Berard, Department of Genetics, Lyon, France.
Sandrine
S
Boyault
Centre Leon Berard, Department of Pathology, Lyon, France.
Sandrine
S
Paindavoine
Centre Hospitalier Universitaire (CHU) de Clermont Ferrand, Department of Pathology, Clermont Ferrand, France.
Pierre Joseph
PJ
Dechelotte
Gustave Roussy, Department of Cancer Medicine, Villejuif, France.|Université Paris Sud, Paris, France.
Benjamin
B
Besse
CHU Nancy, Department of Pathology, Nancy, France.
Jean Michel
JM
Vignaud
Université Claude Bernard Lyon 1, Lyon, France.|Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Pathology, Lyon, France.
Marie
M
Brevet
Université Paris Sud, Paris, France.|Centre Chirurgical Marie Lannelongue, Department of Thoracic Surgery, Le Plessis Robinson, France.
Elie
E
Fadel
Genetics and Biology of Cancer Unit, Institut Curie Research Center, Paris Sciences et Lettres Research University, Paris, France.|Site de Recherche Intégrée en Cancérologie (SiRIC) Institut Curie, Recherche Translationelle en Oncologie Pédiatrique (RTOP), Paris, France.
Wilfrid
W
Richer
Centre Leon Berard, Department of Pathology, Lyon, France.
Isabelle
I
Treilleux
INSERM U830, Institut Curie Research Center, Paris, France.|Institut Curie Hospital Group, Unité de Génétique Somatique, Paris, France.
Julien
J
Masliah-Planchon
Hospices Civils de Lyon, Hôpital de la Croix Rousse, Department of Pathology, Lyon, France.
Mojgan
M
Devouassoux-Shisheboran
CHU Caen, Department of Pneumology and Thoracic Oncology, Caen, France.|Unité Mixte de Recherche (UMR) INSERM U186, Université Caen-Basse Normandie, Caen, France.
Gerard
G
Zalcman
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Plateforme de Ressources Biologiques, Creteil, France.|Université Paris-Est, Créteil, France.|INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.
Yves
Y
Allory
Institut Curie Hospital Group, Unité de Génétique Somatique, Paris, France.|Institut Curie, Département d'Oncologie Pédiatrique, Paris, France.
Franck
F
Bourdeaut
Université Claude Bernard Lyon 1, Lyon, France.|Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Pathology, Lyon, France.
Francoise
F
Thivolet-Bejui
Centre Leon Berard, Department of Pathology, Lyon, France.
Dominique
D
Ranchere-Vince
Université Claude Bernard Lyon 1, Lyon, France.|Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Respiratory Medicine, Lyon, France.
Nicolas
N
Girard
CHU Grenoble, Department of Pathology, Grenoble, France.|Université de Grenoble Joseph Fourier, Grenoble, France.
Sylvie
S
Lantuejoul
CHU Caen, Department of Pathology, Caen, France.|INSERM U1086, Caen, France.
Francoise
F
Galateau-Sallé
Institut Bergonie, Department of Pathology, Bordeaux, France.|Université Bordeaux 2, Bordeaux, France.
Jean Michel
JM
Coindre
Gustave Roussy, INSERM U981, Villejuif, France.|Gustave Roussy, Department of Cancer Medicine, Villejuif, France.
Alexandra
A
Leary
Genetics and Biology of Cancer Unit, Institut Curie Research Center, Paris Sciences et Lettres Research University, Paris, France.|INSERM U830, Institut Curie Research Center, Paris, France.|Institut Curie Hospital Group, Unité de Génétique Somatique, Paris, France.
Olivier
O
Delattre
Cancer Research Center of Lyon, INSERM U1052, Lyon, France.|Université Claude Bernard Lyon 1, Lyon, France.|Centre Leon Berard, Department of Oncology, Lyon, France.
Jean Yves
JY
Blay
Genetics and Biology of Cancer Unit, Institut Curie Research Center, Paris Sciences et Lettres Research University, Paris, France.|INSERM U830, Institut Curie Research Center, Paris, France.
Franck
http://orcid.org/0000-0003-4731-7817
F
Tirode
D000328:Adult; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics*; D013899:Thoracic Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
C501959:BANF1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases