title: Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas.
abstract: Renal medullary carcinoma (RMC) is a rare and highly aggressive neoplasm that most often occurs in the setting of sickle cell trait or sickle cell disease (SCD). Most patients present with metastatic disease resistant to conventional chemotherapy, and therefore there is an urgent need for molecular insight to propose new therapies.
  
  
  
  To determine the molecular alterations and oncogenic pathways that drive RMC development.
  
  
  
  A series of five frozen samples of patients with RMC was investigated by means of gene expression profiling, array comparative genomic hybridization, and RNA and whole exome sequencing (WES).
  
  
  
  RNA and DNA sequencing read data were analyzed to detect gene fusions and somatic mutations. Gene fusions mutations were validated by real-time polymerase chain reaction and fluorescence in situ hybridization. Gene expression profiling was analyzed by unsupervised hierarchical clustering and Gene Set Enrichment Analysis (Broad Institute, Cambridge, MA, USA).
  
  
  
  We observed inactivation of the tumor suppressor gene SMARCB1 in all tumors. In all four cases developed in patients with SCD, we identified an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence and thus contribute to its inactivation. Gene expression profiling revealed that RMC shares common oncogenic pathways with pediatric malignant rhabdoid tumors, another tumor subtype characterized by SMARCB1 deficiency.
  
  
  
  RMCs are characterized by an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence. WES reveals that RMCs show no other recurrent genetic alteration and an overall stable genome, underscoring the oncogenic potency of SMARCB1 inactivation.
  
  
  
  Our comprehensive molecular study supports a pivotal role of the tumor suppressor gene SMARCB1 in the development of renal medullary carcinoma. The use of therapeutic strategies based on the biologic effects of its inactivation should now open new perspectives for this typically lethal malignancy.
authors.affiliation: APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France; INSERM, U955, Institut Mondor de Recherche Biomédicale, Créteil, France; Université Paris-Est Créteil, Créteil, France. Electronic address: juliencalderaro@yahoo.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.affiliation: Institut Curie, Unité de Génétique Somatique, Paris, France; INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Masliah-Planchon
authors.affiliation: INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France; SiRIC Institut Curie, Recherche Translationnelle en Oncologie Pediatrique, Paris, France.
authors.forename: Wilfrid
authors.initials: W
authors.lastname: Richer
authors.affiliation: Institut Curie, Unité de Génétique Somatique, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Maillot
authors.affiliation: APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Maille
authors.affiliation: CHU Nancy, Hôpital d'enfants, Service d'Hémato-oncologie pédiatrique, Vandoeuvre les Nancy, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Mansuy
authors.affiliation: CHU Nancy, Hôpital Brabois, Service d'Anatomie pathologique, Vandoeuvre les Nancy, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bastien
authors.affiliation: INSERM, U955, Institut Mondor de Recherche Biomédicale, Créteil, France; Université Paris-Est Créteil, Créteil, France; APHP, Groupe Hospitalier Henri Mondor, Service d'Urologie, Créteil, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: de la Taille
authors.affiliation: APHP, Groupe Hospitalier Henri Mondor, Service d'Oncologie médicale, Créteil, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Boussion
authors.affiliation: APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Charpy
authors.affiliation: CHU Tours, Hôpital Clocheville, Service d'oncologie et d'hématologie pédiatrique, Tours, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Jourdain
authors.affiliation: CHU Tours, Service d'Anatomie et de cytologie pathologiques, Tours, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bléchet
authors.affiliation: Institut Curie, Unité de Génétique Somatique, Paris, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Pierron
authors.affiliation: Plateforme de Biologie Moléculaire, Département de Recherche Translationnelle, Institut Curie, Centre de Recherche, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.affiliation: APHP, Hôpital Bichat, Département de Pathologie, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Choudat
authors.affiliation: Université Paris-Est Créteil, Créteil, France; APHP, Groupe Hospitalier Henri Mondor, Service d'Oncologie médicale, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tournigand
authors.affiliation: Institut Curie, Unité de Génétique Somatique, Paris, France; INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France; INSERM, U955, Institut Mondor de Recherche Biomédicale, Créteil, France; Université Paris-Est Créteil, Créteil, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
authors.affiliation: INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France; SiRIC Institut Curie, Recherche Translationnelle en Oncologie Pediatrique, Paris, France; Institut Curie, Département d'Oncologie Pédiatrique -Adolescents Jeunes Adultes, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bourdeaut
mesh_terms: D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics; D002154:Calpain / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D002277:Carcinoma / Q000150:complications / Q000235:genetics*; D002648:Child; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D050939:Gene Fusion; D006801:Humans; D007680:Kidney Neoplasms / Q000150:complications / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics; D000071796:SMARCB1 Protein / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic; D000073359:Exome Sequencing
chemical_list: D004268:DNA-Binding Proteins; C557041:MALAT1 long non-coding RNA, human; C471297:MAML2 protein, human; D009687:Nuclear Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D062085:RNA, Long Noncoding; C539738:RORA protein, human; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D002154:Calpain; C569870:CAPN2 protein, human
keywords: Renal medullary carcinoma; SMARCB1; Sickle cell disease; Translocation