Julien Calderaro1, Julien Masliah-Planchon2, Wilfrid Richer3, Laetitia Maillot4, Pascale Maille5, Ludovic Mansuy6, Claire Bastien7, Alexandre de la Taille8, Hélène Boussion9, Cécile Charpy5, Anne Jourdain10, Claire Bléchet11, Gaelle Pierron4, David Gentien12, Laurence Choudat13, Christophe Tournigand14, Olivier Delattre2, Yves Allory15, Franck Bourdeaut16. 1. 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. 2. Institut Curie, Unité de Génétique Somatique, Paris, France; INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France. 3. INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France; SiRIC Institut Curie, Recherche Translationnelle en Oncologie Pediatrique, Paris, France. 4. Institut Curie, Unité de Génétique Somatique, Paris, France. 5. APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France. 6. CHU Nancy, Hôpital d'enfants, Service d'Hémato-oncologie pédiatrique, Vandoeuvre les Nancy, France. 7. CHU Nancy, Hôpital Brabois, Service d'Anatomie pathologique, Vandoeuvre les Nancy, France. 8. 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. 9. APHP, Groupe Hospitalier Henri Mondor, Service d'Oncologie médicale, Créteil, France. 10. CHU Tours, Hôpital Clocheville, Service d'oncologie et d'hématologie pédiatrique, Tours, France. 11. CHU Tours, Service d'Anatomie et de cytologie pathologiques, Tours, France. 12. Plateforme de Biologie Moléculaire, Département de Recherche Translationnelle, Institut Curie, Centre de Recherche, Paris, France. 13. APHP, Hôpital Bichat, Département de Pathologie, Paris, France. 14. Université Paris-Est Créteil, Créteil, France; APHP, Groupe Hospitalier Henri Mondor, Service d'Oncologie médicale, Créteil, France. 15. 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. 16. 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.
Abstract
BACKGROUND: 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. OBJECTIVE: To determine the molecular alterations and oncogenic pathways that drive RMC development. DESIGN, SETTING, AND PARTICIPANTS: 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). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: 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). RESULTS AND LIMITATIONS: 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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.
BACKGROUND: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. OBJECTIVE: To determine the molecular alterations and oncogenic pathways that drive RMC development. DESIGN, SETTING, AND PARTICIPANTS: 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). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: 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). RESULTS AND LIMITATIONS: 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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.
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