Author: "TIRODE, Franck" / Topic: [sdv.bbm.gtp] life sciences [q-bio]/biochemistry, molecular biology/genomics [q-bio.gn] - Searchworks@Jio Institute Digital Library Search Results

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40 results on '"TIRODE, Franck"'

1. Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone

Author: Ali, Naser, Niada, Stefania, Brini, Anna, Morris, Mark, Kurusamy, Sathishkumar, Alholle, Abdullah, Huen, David, Antonescu, Cristina, TIRODE, Franck, Sumathi, Vaiyapuri, Latif, Farida, University of Birmingham [Birmingham], Istituto Ortopedico Galeazzi-IRCCS, Università degli Studi di Milano [Milano] (UNIMI), University of Wolverhampton, Memorial Sloane Kettering Cancer Center [New York], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), TIRODE, Franck, and Università degli Studi di Milano = University of Milan (UNIMI)
Subjects: Databases, Factual, Sequence Analysis, RNA, Gene Expression Profiling, Bone Neoplasms, Cell Differentiation, Sarcoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, Diagnosis, Differential, Fibroblast Growth Factor-23, Phenotype, [SDV.CAN] Life Sciences [q-bio]/Cancer, Predictive Value of Tests, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Mutation, Exome Sequencing, Biomarkers, Tumor, Humans, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetic Predisposition to Disease, Gene Fusion, Transcriptome, Retrospective Studies
Abstract: Undifferentiated pleomorphic sarcoma of bone (UPSb) is a rare primary bone sarcoma that lacks a specific line of differentiation. There is very little information about the genetic alterations leading to tumourigenesis or malignant transformation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, can be challenging due to overlapping features. To explore the genomic and transcriptomic landscape of UPSb tumours, whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) were performed on UPSb tumours. All tumours lacked hotspot mutations in IDH1/2 132 or 172 codons, thereby excluding the diagnosis of dedifferentiated chondrosarcoma. Recurrent somatic mutations in TP53 were identified in four of 14 samples (29%). Moreover, recurrent mutations in histone chromatin remodelling genes, including H3F3A, ATRX and DOT1L, were identified in five of 14 samples (36%), highlighting the potential role of deregulated chromatin remodelling pathways in UPSb tumourigenesis. The majority of recurrent mutations in chromatin remodelling genes identified here are reported in COSMIC, including the H3F3A G34 and K36 hotspot residues. Copy number alteration analysis identified gains and losses in genes that have been previously altered in UPSb or UPS of soft tissue. Eight somatic gene fusions were identified by RNA-Seq, two of which, CLTC-VMP1 and FARP1-STK24, were reported previously in multiple cancers. Five gene fusions were genomically characterised. Hierarchical clustering analysis, using RNA-Seq data, distinctly clustered UPSb tumours from osteosarcoma and other sarcomas, thus molecularly distinguishing UPSb from other sarcomas. RNA-Seq expression profiling analysis and quantitative reverse transcription-polymerase chain reaction showed an elevated expression in FGF23, which can be a potential molecular biomarker for UPSb. To our knowledge, this study represents the first comprehensive WES and RNA-Seq analysis of UPSb tumours revealing novel protein-coding recurrent gene mutations, gene fusions and identifying a potential UPSb molecular biomarker, thereby broadening the understanding of the pathogenic mechanisms and highlighting the possibility of developing novel targeted therapeutics. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.
Published: 2019
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2. Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion

Author: Alholle, Abdullah, Karanian, Marie, Brini, Anna T., Morris, Mark R., Kannappan, Vinodh, Niada, Stefania, Niblett, Angela, Ranchère-Vince, Dominique, Daniel PISSALOUX, Delfour, Christophe, Maran-Gonzalez, Aurelie, Antonescu, Cristina R., Sumathi, Vaiyapuri, Tirode, Franck, Latif, Farida, University of Birmingham [Birmingham], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], University of Milan, Istituto Ortopedico Galeazzi-IRCCS, University of Wolverhampton, Robert Aitken Institute of Clinical Research [Birmingham], Laboratoire d’Anatomie Pathologique [CHU Gui de Chauliac], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Institut du Cancer de Montpellier (ICM), Memorial Sloane Kettering Cancer Center [New York], TIRODE, Franck, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Università degli Studi di Milano = University of Milan (UNIMI)
Subjects: Adult, Male, undifferentiated small round cell sarcoma, Soft Tissue Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Proto-Oncogene Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Cell Proliferation, gene fusion, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Repressor Proteins, HEK293 Cells, Phenotype, Molecular Diagnostic Techniques, Sarcoma, Small Cell, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, RNA-seq, Ewing sarcoma, Transcription Factors
Abstract: In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by reverse transcription polymerase chain reaction, long-range polymerase chain reaction, and fluorescence in situ hybridization. In vitro, we showed that the cells expressing the gene fusion were morphologically distinct and had enhanced oncogenic potential as compared with control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1-positive tumours. Moreover, these analyses indicated enhanced NTRK1 expression in CRTC1-SS18-positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCSs with unique gene signatures, and may be of therapeutic relevance. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.
Published: 2018
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3. Chimeric oncogene regulates the EGR2 sarcoma susceptibility gene via a GGAA-microsatellite

Author: Grünewald, Thomas, Bernard, Virginie, Gilardi-Hebenstreit, Pascale, Raynal, Virginie, Surdez, Didier, Aynaud, Marie-Ming, Cidre-Aranaz, Florencia, Mirabeau, Olivier, TIRODE, Franck, Pérot, Gaëlle, Jonker, Anneliene, Lucchesi, Carlo, Le Deley, Marie-Cécile, Oberlin, Odile, Marec-Bérard, Perrine, Véron, Amélie, Reynaud, Stéphanie, Lapouble, Eve, Boeva, Valentina, Rio Frio, Thomas, Alonso, Javier, Pierron, Gaëlle, Cancel-Tassin, Geraldine, Cussenot, Olivier, Cox, David, Chanock, Stephen, Charnay, Patrick, Delattre, Olivier, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Instituto de Investigacion de Enfermedades Raras [Madrid, Spain], Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pédiatrie, Institut Gustave Roussy (IGR), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Génétique Somatique [Institut Curie, Paris], Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), T.G.P.G. is supported by a grant from the German Research Foundation (DFG GR3728/2-1).D.S. is supported by the Institut Curie–SIRIC (Site de Recherche Intégrée en Cancérologie)program. D.G.C. is supported by a grant from the InfoSarcomes association. Additionally, thiswork was supported by grants from the Institut Curie, the INSERM, the ANR-10-E PX-03from the Agence Nationale de la Recherche (investissements d’avenir), ANR10-INBS-09-08from the Cancerop le Ile-de-France, the Ligue Nationale Contre le Cancer (Equipelabellisée), the Institut National du Cancer (PLBIO14-237), the European PROVABES (ERA649 NET TRANSCAN JTC-2011), ASSET (FP7-HEALTH-2010-259348), and EEC(HEALTH-F2-2013-602856) projects, the Société Française des Cancers de l’Enfant and thefollowing associations: Courir pour Mathieu, Dans les pas du Géant, Olivier Chape, LesBagouzamanon, Enfants et Santé, and les Amis de Claire., TIRODE, Franck, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, EWSR1-FLI1, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], EGR2, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, germline susceptibility, Ewing sarcoma, GGAA- microsatellite
Abstract: International audience; Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis
Published: 2015
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4. Neonatal Soft Tissue Sarcoma with YWHAE-NUTM2B Fusion

Author: Maylis Guizard, Marie Karanian, Nadège Corradini, Amine Bouhamama, Cécile Faure-Conter, Franck Tirode, Frédérique Dijoud, Frédéric Hameury, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), TIRODE, Franck, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Stromal cell, Cancer biology, Case Report, [SDV.CAN]Life Sciences [q-bio]/Cancer, Chromosomal translocation, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC254-282, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neonatal, medicine, Chemotherapy, YWHAE, business.industry, Soft tissue sarcoma, Soft tissue, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sarcoma, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030104 developmental biology, Oncology, Fusion transcript, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], business
Abstract: International audience; Neonatal soft tissues sarcoma is a rare entity that comprises heterogeneous types of tumors. In this article we describe a neonatal case of round-cell sarcoma with an YWHAE-NUTM2B fusion gene. The patient was treated just after birth with neoadjuvant chemotherapy, then surgical resection, but evolution was quickly fatal. This fusion transcript has been reported in endometrial stromal sarcomas and clear cells renal sarcomas but its description in small round-cell sarcomas is recent. To our knowledge, this is the first case report describing this translocation in a newborn patient with soft tissues sarcoma and its clinical tumoral evolution.
Published: 2019
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5. Very long‐term survivors among patients with metastatic soft tissue sarcoma

Author: Isabelle Ray-Coquard, Pierre Meeus, Jean-Yves Blay, Marie Karanian, Mehdi Brahmi, Amine Bouhamama, Daniel Pissaloux, Franck Tirode, Armelle Dufresne, Camille Schiffler, Marie-Pierre Sunyach, Gualter Vaz, Mélodie Carbonnaux, TIRODE, Franck, Centre Léon Bérard [Lyon], Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, Disease, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 0302 clinical medicine, Medicine, Prospective Studies, Stage (cooking), Neoplasm Metastasis, Original Research, Incidence (epidemiology), Soft tissue sarcoma, long‐term survivors, Incidence, Age Factors, Soft tissue, Sarcoma, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Synovial sarcoma, 3. Good health, metastatic sarcomas, 030220 oncology & carcinogenesis, long-term survivors, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, soft tissue sarcomas, lcsh:RC254-282, 03 medical and health sciences, Young Adult, Sex Factors, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], clinico-pathological characteristics, Humans, Radiology, Nuclear Medicine and imaging, Aged, Endometrial stromal sarcoma, Performance status, business.industry, Clinical Cancer Research, prognostic factors, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, 030104 developmental biology, Logistic Models, Neoplasm Grading, business
Abstract: International audience; Background: Metastatic soft tissue sarcomas (STS) are a group of rare and heterogeneous mesenchymal tumors with a poor prognosis. The aim of this study was to evaluate the incidence of long-term survivors and describe their presentation and management in a large cohort of patients with metastatic STS.Methods: We collected information of patients with metastatic STS managed in Centre Leon Berard between 1985 and 2015 aiming to compare the group of patients alive 5 years after the diagnosis of metastases vs the others. Prognostic factors of patients and tumors characteristics were investigated by logistic regression analysis. For "long-term survivors," we explored therapeutic strategies at metastatic stage.Results: Out of 436 patients enrolled, 39 (9%) were still alive 5 years after diagnostic of metastases with a median survival of 146 months (12 years). This "long-term survivors" group included more female and younger patients, with better performance status, more synovial sarcoma or endometrial stromal sarcoma, more patients with simple genomic sarcomas, lower tumor grade, smaller tumor, and longer disease-free interval. In multivariate analysis, age below 55 at metastatic stage (P = 0.0002) and grade 1 tumor (P < 0.0001) were significantly associated with the "long-term survivors." Their therapeutic management was usually aggressive (intensified or polychemotherapy, repeated local treatment of metastases), leading to 62% of complete response in first-line setting.Conclusions: Very long-term survivors are observed in metastatic STS. Selection of patients in good condition with less aggressive tumor and administration of intensive treatment may lead to obtain these motivating results in a poor prognosis disease.
Published: 2019
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6. SRF-FOXO1 and SRF-NCOA1 Fusion Genes Delineate a Distinctive Subset of Well-differentiated Rhabdomyosarcoma

Author: Nadège Corradini, Jean-Yves Blay, Adeline Duc-Gallet, Marie-Pierre Castex, Franck Tirode, Véronique Minard, Daniel Pissaloux, François Le Loarer, Carole Chevenet, Anne Gomez-Brouchet, Carla Fernandez, Marie Karanian, TIRODE, Franck, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie Pathologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut Bergonié [Bordeaux], UNICANCER, Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'oncologie pédiatrique [CHU Toulouse], and CHU Toulouse [Toulouse]
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Serum Response Factor, Paraspinal Muscles, [SDV.CAN]Life Sciences [q-bio]/Cancer, In situ hybridization, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Pathology and Forensic Medicine, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, Nuclear Receptor Coactivator 1, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neck Muscles, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Rhabdomyosarcoma, medicine, Adjuvant therapy, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Nuclear atypia, In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, Forkhead Box Protein O1, Sequence Analysis, RNA, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Differentiation, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, Treatment Outcome, PTCH1, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Surgery, Female, Anatomy, Gene Fusion, Comparative genomic hybridization
Abstract: International audience; Rhabdomyosarcoma (RMS) encompasses a heterogenous collection of tumors in which new groups have recently been identified that improved the World Health Organization (WHO) classification. While performing RNA-sequencing in our routine practice, we identified 3 cases of well-differentiated RMS harboring new fusion genes. We also analyzed these tumors through array-comparative genomic hybridization. Clinically, these tumors were deep paraspinal tumors, occurring in neo-nat and young children. The patients underwent resection and adjuvant therapy. At the time of last follow-up (ranging from 12 to 108 mo), they were alive without disease. Histologically, these tumors consisted of well-differentiated rhabdomyoblastic proliferations with nuclear atypia, infiltrative borders, and a specific growth pattern. These tumors harbored new fusion genes involving SRF and either FOXO1 or NCOA1. We compared the expression profiles of these 3 tumors to the expression data of a series of 33 skeletal muscle tumors including embryonal RMSs, alveolar rhandomyosarcomas, RMSs with VGLL2 fusions, RMSs with the myoD1 mutation, EWSR1/FUS-TFCP2 epithelioid and spindle cell RMSs of the bone, and rhabdomyomas with PTCH1 loss. According to clustering analyses, the 3 SRF-fused tumors formed a distinct group with a specific expression profile different from that of the other types of skeletal muscle tumors. Array-comparative genomic hybridization showed a recurrent gain of chromosome 11. These 3 tumors define a new group of RMS associated with a fusion of the SRF gene. FOXO1 rearrangements, usually used to confirm the diagnosis of alveolar RMS and identify poor-outcome RMSs, were identified in a nonalveolar RMS for the first time.
Published: 2020
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7. A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation

Author: Benjamin Bonhomme, Cleofe Romagosa, Gaëlle Pierron, Anne Moreau, Jean Michel Coindre, Arjen H.G. Cleven, Irma Ramos-Oliver, François Le Loarer, Sophie Le Guellec, Corinne Bouvier, Sébastien Salas, Anne Gomez-Brouchet, Virginie Audard, Marie Pierre Castex, Frédérique Larousserie, Anand Sherwood, Anne-Marie Cleton-Jansen, Dilara C. Savci-Heijink, Camille Laurent, Franck Tirode, Judith V.M.G. Bovée, Daniel Pissaloux, Jessica Baud, Antoine Giraud, Herman M. Kroon, Institut Bergonié [Bordeaux], UNICANCER, Université de Bordeaux (UB), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Leiden University Medical Center (LUMC), Département de pathologie [CHU La Timone, Marseille], Hôpital de la Timone [CHU - APHM] (TIMONE), Département d'oncologie pédiatrique [CHU Toulouse], CHU Toulouse [Toulouse], Vall d'Hebron University Hospital [Barcelona], Service de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie [AP-HP Hôpital Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biologie des Tumeurs, Institut Curie [Paris], Department of Conservative Dentistry and Endodontics [CSI College of Dental Sciences, Madurai, India], Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and TIRODE, Franck
Subjects: Male, 0301 basic medicine, Pathology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Fusion gene, 0302 clinical medicine, CDKN2A, Rhabdomyosarcoma, Anaplastic Lymphoma Kinase, Prospective Studies, Child, Exome, Aged, 80 and over, medicine.diagnostic_test, Epithelioid Cells, Soft tissue, Middle Aged, Prognosis, Immunohistochemistry, Up-Regulation, 3. Good health, DNA-Binding Proteins, Phenotype, Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Sarcoma, Gene Fusion, Adult, medicine.medical_specialty, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Craniofacial, Retrospective Studies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, 030104 developmental biology, Transcription Factors, Fluorescence in situ hybridization
Abstract: International audience; Rhabdomyosarcomas with TFCP2 fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2 break-apart probe (n = 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer® FusionPlex® Sarcoma kit). Patient's age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n = 12/14) and soft tissue (n = 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n = 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALK fusion on break-apart FISH (n = 5) nor next-generation sequencing (n = 14). ALK upregulation was frequently associated with an internal deletion at genomic level. TFCP2 was fused in 5' either to EWSR1 (n = 6) or FUS (n = 8). EWSR1 was involved in both soft tissue cases. FISH with TFCP2 break-apart probe was positive in all tested cases (n = 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2A deletions. FET-TFCP2 rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2 rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.
Published: 2020
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8. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author: Ana Patiño-García, Thomas G. P. Grunewald, David G. Cox, Lindsay M. Morton, Michelle Manning, Sandrine Grossetête-Lalami, Gaëlle Pierron, Nadège Corradini, Stephen J. Chanock, Kathleen Wyatt, Udo Kontny, Gregory T. Armstrong, Jean Michon, Sakina Zaidi, Didier Surdez, Wolfgang Hartmann, Heinrich Kovar, Olivier Delattre, Jennifer Kriebel, Nathalie Gaspar, Perrine Marec Bérard, Valérie Laurence, Casey L. Dagnall, Thomas Kirchner, Stéphanie Reynaud, Uta Dirksen, Nathaniel Rothman, Konstantin Strauch, Margaret A. Tucker, Lisa Mirabello, Smita Bhatia, Markus Metzler, Laurie Burdett, Neal D. Freedman, Rebeca Alba Rubio, Franck Tirode, Andreas E. Kulozik, Meredith Yeager, Kristine Jones, Javier Alonso, Stelly Ballet, Olivier Mirabeau, Eve Lapouble, Robert N. Hoover, Weiyin Zhou, Wendy M. Leisenring, Leslie L. Robison, Piero Picci, Javed Khan, Thomas Meitinger, Anna González-Neira, Eric Karlins, Mitchell J. Machiela, Unión Europea, TIRODE, Franck, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Laboratory for Pediatric Sarcoma Biology [Munich, Germany], Ludwig-Maximilian-Universität München Pathologisches Institut [Germany], German Cancer Consortium [Heidelberg] (DKTK), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unité de Génétique Somatique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research (FNLCR), Unité de Génétique Somatique [Institut Curie, Paris], Children’s Cancer Research Institute [Vienna, Austria], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Division of Pediatric Hematology, Oncology and Stem Cell Transplantation [Aechen, Germany], Genotyping Unit (CeGen), Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Istituto Ortopedico Rizzoli [Bologna, Italy], Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Epidemiology and Cancer Control [Memphis, TN, USA], Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA], Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA], University Children's Hospital of Heidelberg [Heidelberg, Germany], Research Unit of Molecular Biology [Neuherberg, Germany], Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Diseases [Neuherberg, Germany] (DZD), Institute of Human Genetics [Neuherberg] (IHG), Helmholtz Zentrum München = German Research Center for Environmental Health, Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen = Uniklinikum Erlangen, Gerhard-Domagk-Institute of Pathology, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Genetic Epidemiology [Neuherberg, Germany], Chair of Genetic Epidemiology [Munich, Germany] (IBE), Institute of Pathology [Munich, Germany], University Children's Hospital of Essen [Essen, Germany], This work was supported by the Intramural Research Program of the U.S. NationalCancer Institute and the Intramural Research Program of the American Cancer Society.This work was supported by grants from the Institut Curie, the Inserm, the LigueNationale Contre le Cancer (Equipe labellisée, Carte d’Identité des Tumeurs programand Recherche Epidémiologique 2009 program), the ANR-10-EQPX-03 from the AgenceNationale de la Recherche, the European PROVABES (ERA-649 NET TRANSCAN JTC2011), and ASSET (FP7-HEALTH-2010-259348) projects. This research was supportedby FP7 grant 'EURO EWING Consortium' No. 602856 and the following associations:Courir pour Mathieu, Dans les pas du Géant, Les Bagouzamanon, Enfants et Santé, M lavie avec Lisa, Lulu et les petites bouilles de lune, les Amis de Claire, l’Etoile de Martin andthe Société Française de lutte contre les Cancers et les leucémies de l’Enfant et del’adolescent. The laboratory of T. G. P. Grünewald is supported by grants from the‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultätder LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMU excellentwithin the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the WilhelmSander-Foundation (2016.167.1), and by the German Cancer Aid (DKH-111886 andDKH-70112257). D. Surdez is supported by SiRIC (Grant « INCa-DGOS-4654). Wethank the following clinicians for providing samples used in this study: C. Alenda, F.Almazán, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Beléndez, C. Berger, C. Bergeron, P. Biron, J.Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D.Chauveaux, C. Calvo, A. Carboné, C. Clement, T. Contra, N. Corradini, A.S. Defachelles,V. Gandemer-Delignieres, A. Deville, A. Echevarria, J. Fayette, M. Fraga, D. Frappaz, J.L.Fuster, P. García-Miguel, J.C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O.Lejars, R. López-Almaraz, B. López-Ibor, P. Lutz, J.F. Mallet, L. Mansuy, P. Marec Bérard,G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G.Margueritte, C. Mata, M.E. Mateos, M. Melo, C. Moscardó, M. Munzer, B. Narciso, A.Navajas, D. Orbach, C. Oudot, H. Pacquement, C. Paillard, Y. Perel, T. Philip, C. Piguet,M.I. Pintor, D. Plantaz, E. Plouvier, S. Ramirez-Del-Villar, I. Ray-Coquard, Y. Reguerre,M. Rios, P. Rohrlich, H. Rubie, A. Sastre, G. Schleiermacher, C. Schmitt, P. Schneider, L.Sierrasesumaga, C. Soler, N. Sirvent, S. Taque, E. Thebaud, A. Thyss, R. Tichit, J.J. Uriz, J.P. Vannier, F. Watelle-Pichon. This work was supported by the Instituto de SaludCarlos III (PI16CIII/00026) and the Asociación Pablo Ugarte, Fundación Sonrisa deAlex, ASION-La Hucha de Tomás, Sociedad Española de Hematología y OncologíaPediátricas. The Childhood Cancer Survivor Study is supported by the NationalCancer Institute (CA55727, G.T. Armstrong, Principal Investigator), with funding forgenotyping from the Intramural Research Program of the National Institutes ofHealth, National Cancer Institute. The KORA study was initiated and financed by theHelmholtz Zentrum München—German Research Center for Environmental Health,which is funded by the German Federal Ministry of Education and Research (BMBF) andby the State of Bavaria. Furthermore, KORA research was supported within the MunichCenter of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part ofLMUinnovativ, Helmholtz-Zentrum München (HZM), University Hospital Erlangen [Germany], Westfälische Wilhelms-Universität Münster (WWU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Candidate gene, Oncogene Proteins, Fusion, Medizin, General Physics and Astronomy, Genome-wide association study, Cell Cycle Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Science, Genetics, Multidisciplinary, Nuclear Proteins, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Homeobox Protein Nkx-2.2, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quality Control, Risk, Genotype, Science, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Genetic Predisposition to Disease, Allele, Alleles, Cell Proliferation, Homeodomain Proteins, Proto-Oncogene Protein c-fli-1, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Zebrafish Proteins, Pediatric cancer, 030104 developmental biology, Expression quantitative trait loci, lcsh:Q, RNA-Binding Protein EWS, Transcription Factors, Genome-Wide Association Study
Abstract: Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk., Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.
Published: 2018
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9. Molecular classification of endometrial stromal sarcomas using RNA sequencing defines nosological and prognostic subgroups with different natural history

Author: Marie Karanian, Alexandra Meurgey, Franck Tirode, Pierre Meeus, Isabelle Ray-Coquard, Tatiana Franceschi, Amine Bouhamama, Mehdi Brahmi, Isabelle Treilleux, Armelle Dufresne, Mélodie Carbonnaux, Daniel Pissaloux, Jean-Yves Blay, Hélène Vanacker, Marie-Pierre Sunyach, Département d'Oncologie Médicale [Lyon] ( Centre Léon Bérard), Centre Léon Bérard [Lyon], Service de Pathologie [Centre Leon Berard], Département de Biopathologie, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Département d'anatomopathologie, biopathologie, Département de Radio-Oncologie [CLB, Lyon] (Centre Léon Bérard), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogénèse et progression tumorale, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and TIRODE, Franck
Subjects: 0301 basic medicine, Cancer Research, Stromal cell, sarcoma, RNA-sequencing, [SDV.CAN]Life Sciences [q-bio]/Cancer, Chromosomal rearrangement, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Prognostic, lcsh:RC254-282, Article, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Missense mutation, YWHAE, Gene, Endometrial stromal sarcoma, Gene fusions, uterine, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, expression profile, 030104 developmental biology, Oncology, Endometrial stromal sarcomas, 030220 oncology & carcinogenesis, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Sarcoma
Abstract: Simple Summary In about half of the cases, endometrial stromal sarcomas lack the canonical oncogenic fusions JAZF1-SUZ12 or YWHAE-NUTM2, which are mutually exclusive. The aim of this study was to explore by RNA sequencing a retrospective series of uterine sarcomas diagnosed as endometrial stromal sarcomas but negative for JAZF1 and/or YWHAE rearrangement in FISH, in order to provide a better description of their molecular landscape, improve the classification of endometrial stromal sarcomas and provide guidance for disease management. Abstract A series of 42 patient tumors diagnosed as endometrial stromal sarcoma (ESS) based on the morphology but negative for JAZF1 and/or YWHAE rearrangement in FISH was analyzed by RNA-sequencing. A chromosomal rearrangement was identified in 31 (74%) of the cases and a missense mutation in known oncogenes/tumor suppressor genes in 11 (26%). Cluster analyses on the expression profiles from this series together with a control cohort composed of five samples of low grade ESS harboring a JAZF1-SUZ12 fusion, one high grade ESS harboring a BCOR-ITD, two uterine tumors resembling ovarian sex cord tumors, two samples each of uterine leiomyoma and leiomyosarcomas and a series of BCOR-rearranged family of tumor (n = 8) indicated that tumors could be gather in three distinct subgroups: one mainly composed of BCOR-rearranged samples that contained seven ESS samples, one mainly composed of JAZF1-fused ESS (n = 15) and the last composed of various molecular subtypes (n = 19). These three subgroups display different gene signatures, different in silico cell cycle scores and very different clinical presentations, natural history and survival (log-rank test, p = 0.004). While YWHAE-NUTM2 fusion genes may be present in both high and low grade ESS, the high-grade presents with additional BCOR or BCORL1 gene mutations. RNAseq brings clinically relevant molecular classification, enabling the reclassification of diseases and the guidance of therapeutic strategy.
Published: 2020
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10. Brain tumor with an ATXN1-NUTM1 fusion gene expands the histologic spectrum of NUTM1-rearranged neoplasia

Author: Charlotte Dubucs, Aurore Siegfried, Emmanuelle Uro-Coste, Gaëlle Pierron, I. Catalaa, Marion Gambart, Julien Masliah-Planchon, Badreddine Mohand-Oumoussa, Franck Tirode, Sarah Péricart, Franck Bourdeaut, Franck-Emmanuel Roux, Delphine Larrieu-Ciron, Yvan Nicaise, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut Curie, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), TIRODE, Franck, Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: medicine.medical_specialty, Pathology, Neurology, CIC-ATXN1-ATXN1L axis, DNA methylation-based classification, Central nervous system, Brain tumor, Oncogenic gene fusions, CIC-ATXN1-ATXN1L axis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC346-429, Pathology and Forensic Medicine, Fusion gene, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ATXN1, medicine, Letter to the Editor, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, NUTM1-rearranged neoplasia, RNA sequencing, NUTM1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Oncogenic gene fusions, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neurology (clinical)
Abstract: International audience
Published: 2019
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11. Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations

Author: Aurélie Houlier, Philip E. LeBoit, Marie Karanian, Boris C. Bastian, Timothy H. McCalmont, Ingrid Masse, Franck Tirode, Iwei Yeh, Laura B. Pincus, Arnaud de la Fouchardière, Daniel Pissaloux, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], University of California [San Francisco] (UCSF), University of California, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC), and TIRODE, Franck
Subjects: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Skin Neoplasms, Adolescent, Oncogene Proteins, Fusion, Sentinel lymph node, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MAP3K8, Pathology and Forensic Medicine, Fusion gene, 03 medical and health sciences, Exon, Young Adult, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, CDKN2A, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Nevus, Epithelioid and Spindle Cell, Proto-Oncogene Proteins, Biopsy, medicine, Humans, Child, medicine.diagnostic_test, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Middle Aged, medicine.disease, MAP Kinase Kinase Kinases, Spitz nevus, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Comparative genomic hybridization
Abstract: International audience; We report a series of 33 skin tumors harboring a gene fusion of the MAP3K8 gene, which encodes a serine/threonine kinase. The MAP3K8 fusions were identified by RNA sequencing in 28 cases and by break-apart FISH in five cases. Cases in which fusion genes were fully characterized demonstrated a fusion of the 5' part of MAP3K8 comprising exons 1-8 in frame to one of several partner genes at the 3' end. The fusion genes invariably encoded the intact kinase domain of MAP3K8, but not the inhibitory domain at the C-terminus. In 13 (46%) of the sequenced cases, the 3' fusion partner was SVIL. Other recurrent 3' partners were DIP2C and UBL3, with additional fusion partners that occurred only in a single tumor. Clinically, the lesions appeared mainly in young adults (2-59 years of age; median = 18), most commonly involving the lower limbs (55%). Five cases were diagnosed as Spitz nevus, 13 as atypical Spitz tumor, and 15 as malignant Spitz tumor. Atypical and malignant cases more commonly occurred in younger patients. Atypical Spitz tumors and malignant Spitz tumors cases tended to show epidermal ulceration (32%), a dermal component with giant multinucleated cells (32%), and clusters of pigmented cells in the dermis (32%). Moreover, in atypical and malignant cases, a frequent inactivation of CDKN2A (21/26; 77%) was identified either by p16 immunohistochemistry, FISH, or comparative genomic hybridization. Gene expression analysis revealed that MAP3K8 expression levels were significantly elevated compared to a control group of 57 Spitz lesions harboring other known kinase fusions. Clinical follow-up revealed regional nodal involvement in two of six cases, in which sentinel lymph node biopsy was performed but no distant metastatic disease after a median follow-up time of 6 months.
Published: 2019
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12. Malignant melanoma with areas of rhabdomyosarcomatous differentiation arising in a giant congenital nevus with RAF1 gene fusion

Author: Marzak Metref, Arnaud de la Fouchardière, Fatma Boukendakdji, Marie Karanian, Aicha Salhi, Djazia Dahlouk, Aline Baltres, Fateh Allaoua, Salim Ysmail‐Dahlouk, Assya Djeridane, Véronique Haddad, Sylvie Fraitag, Daniel Pissaloux, Franck Tirode, Aurélie Houlier, Centre Léon Bérard [Lyon], Faculté de médecine d'Alger, Université d'Alger 1 (Benyoucef Benkhedda), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Central Hospital of Army [Algiers], Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and TIRODE, Franck
Subjects: 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Pathology, medicine.medical_specialty, RAF1 fusion, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Biochemistry, Genetics and Molecular Biology, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, giant congenital nevus, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Nevus, skin and connective tissue diseases, rhabdomyosarcomatous differentiation, Melanoma, Nodule (medicine), [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, 030104 developmental biology, Oncology, Small-cell melanoma, 030220 oncology & carcinogenesis, Giant Congenital Nevus, Immunohistochemistry, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine.symptom, congenital melanoma, small-cell melanoma
Abstract: International audience; A girl, born with a posterior lumbosacral giant congenital nevus, developed a central nodule that expanded over a period of 14 months into a 10-cm pedunculated mass. Histological analysis of the mass revealed melanoma of myxoid, small round-cell type with areas of rhabdomyosarcomatous transformation confirmed by immunohistochemistry. RNA sequencing identified an in-frame SASS6(e14)-RAF1(e8) fusion in both components and the nevus. A RAF1 FISH break-apart test found a balanced rearrangement pattern in the nevus and an unbalanced pattern in the malignant areas. Wild-type status of NRAS and BRAF was confirmed by NGS techniques. The array-CGH profile displayed copy number alterations commonly found in rhabdomyosarcomas. Despite intensive treatment, widespread metastatic evolution of the melanomatous component was observed.
Published: 2019
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13. Clinicopathologic and Molecular Features of a Series of 41 Biphenotypic Sinonasal Sarcomas Expanding Their Molecular Spectrum

Author: Michel Wassef, Marie Karanian, Frédéric Chibon, Isabelle Hostein, Sophie Le Guellec, Tom Lesluyes, Jean-Michel Coindre, Brigitte Le Bail, Isabelle Soubeyran, Gaëlle Pérot, Franck Tirode, Jessica Baud, Sophie Laffont, Lucile Delespaul, François Le Loarer, Claire Castain, Cristina R. Antonescu, Anne-Catherine Baglin, Valérie Costes-Martineau, Sandrine Eimer, Institut Bergonié [Bordeaux], UNICANCER, Université de Bordeaux (UB), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Memorial Sloane Kettering Cancer Center [New York], Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Bordeaux [Bordeaux], Institut Bergonié - CRLCC Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux, Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), CRLCC Institut Claudius Regaud, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and TIRODE, Franck
Subjects: 0301 basic medicine, Nasal cavity, Male, Pathology, Oncogene Proteins, Fusion, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, S100 protein, Fusion gene, Nuclear Receptor Coactivator 2, 0302 clinical medicine, Paranasal Sinuses, Paired Box Transcription Factors, Prospective Studies, In Situ Hybridization, Fluorescence, Sanger sequencing, Aged, 80 and over, medicine.diagnostic_test, Cell Differentiation, Sarcoma, Middle Aged, musculoskeletal system, Immunohistochemistry, 3. Good health, medicine.anatomical_structure, Phenotype, 030220 oncology & carcinogenesis, embryonic structures, symbols, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Anatomy, Gene Fusion, Nasal Cavity, Paranasal Sinus Neoplasms, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, In situ hybridization, Biology, Article, Pathology and Forensic Medicine, 03 medical and health sciences, symbols.namesake, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, PAX3 Transcription Factor, Aged, MyoD Protein, Retrospective Studies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, 030104 developmental biology, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Trans-Activators, Surgery, Fluorescence in situ hybridization
Abstract: International audience; Biphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor.
Published: 2019
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14. SMARCA4-deficient Thoracic Sarcomas: Clinicopathologic Study of 30 Cases With an Emphasis on Their Nosology and Differential Diagnoses

Author: Fabien Forest, Jean-Michel Coindre, Violaine Yvorel, Daniel Pissaloux, Stéphane Garcia, Marie Brevet, Jean-Yves Blay, Franck Tirode, Sylvie Lantuejoul, François Le Loarer, Sarah Watson, Julien Masliah-Planchon, Vincent Thomas de Montpréville, Lara Chalabreysse, Raul Perret, Isabelle Serre, Institut Bergonié [Bordeaux], UNICANCER, Hospices Civils de Lyon (HCL), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Nord [CHU - APHM], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Léon Bérard [Lyon], Centre Chirurgical Marie Lannelongue (CCML), Centre chirurgical Marie Lannelongue, Unité de Génétique Somatique, Institut Curie [Paris], Université Joseph Fourier - Grenoble 1 (UJF), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de Pathologie, UNICANCER-UNICANCER, Université de Bordeaux (UB), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), TIRODE, Franck, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Nosology, Adult, Male, Pathology, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Chromatin remodeling, Pathology and Forensic Medicine, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Biomarkers, Tumor, Humans, Medical diagnosis, Aged, Aged, 80 and over, business.industry, Clinical course, DNA Helicases, Nuclear Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sarcoma, Middle Aged, Thoracic Neoplasms, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, SMARCA4, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Surgery, Female, Anatomy, business, Transcription Factors
Abstract: International audience; SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity with an aggressive clinical course and specific genetic alterations of the BAF chromatin remodeling complex. In the present study, we reviewed the clinical and pathologic features of 30 cases of SMARCA4-DTS, discussed its main differential diagnoses and the challenging diagnostic scenarios that the average pathologist may face. In addition, we tested the specificity of the "SMARCA4-DTS immunohistochemical signature" (co-loss of SMARCA4 and SMARCA2 with overexpression of SOX2) in a large cohort of intrathoracic malignancies. Patients ranged from 28 to 90 years of age (median: 48 y), with a marked male predominance (male:female=9:1) and they were usually smokers. Tumors were generally large compressive masses located in the mediastinum (n=13), pleura (n=5), lung (n=2) or in 2 or more of these topographies (n=10). Treatment strategies were varied, including 1 case treated with EZH2 inhibitors. Median overall survival was 6 months. Histologically, tumors were poorly differentiated frequently showing rhabdoid features. A subset of cases showed a focal myxoid stroma (7%, n=2/30) and rare cases displayed a previously unreported pattern simulating desmoplastic small round cell tumors (7%, n=2/30). Making a diagnosis was challenging when dealing with biopsy material from massively necrotic tumors and in this setting the expression of SOX2, CD34, and SALL4 proved useful. All tested cases displayed concomitant loss of SMARCA4 and SMARCA2 and most tumors expressed epithelial markers (Pan-keratin or EMA) (n=29/30), SOX2 (n=26/27), and CD34 (n=17/27). SMARCB1 expression was retained in all cases (23/23). SALL4 and Claudin-4 were expressed in a subset of cases (n=7/21 and 2/19, respectively). TTF-1 and P63 were focally expressed in 1 case each. P40 and NUT were not expressed (0/23 and 0/20, respectively) The SMARCA4-DTS immunohistochemical signature was both sensitive and specific, with only a subset of small cell carcinoma of the ovary hypercalcemic type showing overlapping phenotypes. Our study confirms and expands the specific features of SMARCA4-DTS, emphasizing the fact that they can be straightforwardly identified by pathologists.
Published: 2018
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15. PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis

Author: Franck Tirode, Genevieve C. Kendall, James F. Amatruda, Lin Xu, Collette A LaVigne, Stephen X. Skapek, Dinesh Rakheja, Olivier Delattre, Sarah Watson, Whitney Murchison, Department of Pediatrics [Dallas, TX, USA], Department of Molecular Biology [Dallas, TX, USA], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology [Dallas], University of Texas Southwestern Medical Center [Dallas], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Unité de Génétique Somatique [Institut Curie, Paris], Department of Internal Medicine [Dallas, TX, USA], Cancer Prevention and Research Institute of Texas, American Association for Cancer Research, ALex's Lemonade Stand Foundation for Childhood Cancer, Hartwell Foundation, Ligue National contre le Cancer., TIRODE, Franck, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, sarcoma, Mouse, muscle, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Myocyte, Biology (General), Rhabdomyosarcoma, Zebrafish, Cancer Biology, General Neuroscience, PAX3-FOXO1, General Medicine, musculoskeletal system, 3. Good health, embryonic structures, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Sarcoma, Stem cell, Research Article, Human, endocrine system, QH301-705.5, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, fusion oncogene, General Immunology and Microbiology, Cell growth, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, biology.organism_classification, body regions, 030104 developmental biology, Developmental Biology and Stem Cells, HES3, Cancer research, rhabdomyosarcoma, Carcinogenesis
Abstract: Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1 fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6–19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target. Ectopic expression of the her3 human ortholog, HES3, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, HES3 is overexpressed in fusion-positive versus fusion-negative tumors. Finally, HES3 overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new PAX3-FOXO1 target, her3/HES3, that contributes to impaired myogenic differentiation and has prognostic significance in human disease., eLife digest One of the most common cancers in children and adolescents is rhabdomyosarcoma, a cancer of soft tissue such as muscle, tendon or cartilage. The fusion of DNA on two different chromosomes causes the most aggressive form of rhabdomyosarcoma. The fused DNA produces an abnormal protein called PAX3-FOXO1. During normal muscle development, a subset of rapidly growing cells eventually slow down and form mature, working muscle cells. It is still unclear how exactly rhabdomyosarcoma develops, but it is thought that PAX3-FOXO1 stops muscle cells from maturing and the cells that grow out of control result in a tumor. Learning how PAX3-FOXO1 hijacks normal muscle development could lead to new treatments for rhabdomyosarcoma. One treatment approach is to slow the growth of a tumor and force the cells to mature. Then, young patients might avoid chemotherapy or radiation treatments and their side effects. Efforts to improve treatment for this type of cancer face several obstacles. Currently, only one vertebrate animal model of the disease is available to test drugs, and it is still not known how PAX3-FOXO1 causes healthy cells to become cancerous. It is also hard to turn off PAX3-FOXO1 itself, so scientists must find additional proteins that collaborate with it to target with drugs. Now, Kendall et al. show that genetically engineered zebrafish with human PAX3-FOXO1 develop rhabdomyosarcoma-like tumors. Experiments on these zebrafish showed that the protein turns on a gene called her3. Humans have a similar gene called HES3. In zebrafish or mouse cells, human HES3 interferes with muscle-cell maturation and allows cells that acquire PAX3-FOXO1 to persist during development instead of dying. It also increases the cell growth and cancerous behavior in human tumor cells. Kendall et al. further looked at HES3 levels in tumors collected from patients with rhabdomyosarcoma and found that having higher levels of HES3 increased the risk of death from the cancer. Human rhabdomyosarcoma tumors with high HES3 levels were also more likely to have certain cell-growth and cell-differentiation related proteins. Drugs that turn off or modify the activity of these proteins already exist. Testing these drugs that target processes such as cell growth in the zebrafish with rhabdomyosarcoma-like tumors may help scientists determine if they reduce tumor growth. If they do, additional trials could determine if they would help patients with rhabdomyosarcoma.
Published: 2018
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16. Transcriptomic definition of molecular subgroups of small round cell sarcomas

Author: Delphine Guillemot, Megane Bouvet, Sarah Watson, Paul Fréneaux, Jean-Michel Coindre, Jean-Marc Guinebretière, Louise Galmiche-Rolland, Dominique Ranchère-Vince, Stéphanie Reynaud, Franck Tirode, Olivier Delattre, Frédérique Larousserie, Elisabeth Longchampt, Marie Karanian, Gaëlle Pierron, François Le Loarer, Virginie Perrin, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Unité de Génétique Somatique, Institut Bergonié [Bordeaux], UNICANCER, Université de Bordeaux (UB), Centre Léon Bérard [Lyon], Hôpital René HUGUENIN (Saint-Cloud), Service de pathologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Hôpital Foch [Suresnes], Equipe labellisée Ligue contre le Cancer, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and TIRODE, Franck
Subjects: 0301 basic medicine, FET-TFCP2, sarcoma, Oncogene Proteins, Fusion, Muscle Proteins, Bone Neoplasms, VGLL2-NCOA2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Pathology and Forensic Medicine, Transcriptome, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, DUX4, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene duplication, medicine, Round cell, Biomarkers, Tumor, Humans, FUS-NFATC2, Gene, fusion genes, EWSR1-PATZ1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, RNAseq, DNA-Binding Proteins, Repressor Proteins, 030104 developmental biology, 030220 oncology & carcinogenesis, Sarcoma, Small Cell, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], CIC-fused, Spindle cell sarcoma, Sarcoma, Gene Fusion, BCOR-rearranged, Transcription Factors
Abstract: Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Published: 2018
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17. Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions

Author: Franck Tirode, A. Michot, Gaëtan MacGrogan, Daniel Pissaloux, Yanis Zekri, Jean-Yves Blay, Tom Lesluyes, Florence Pedeutour, Dominique Ranchère-Vince, Frédéric Chibon, Lucile Delespaul, Agnès Lancon, Frédérique Keslair, Ilaria Di Mauro, Jean-Michel Coindre, Arnaud de la Fouchardière, Marie Karanian, Nathalie Cardot-Leccia, François Le Loarer, Laurent Alberti, Gaëlle Pérot, Adeline Duc, Sandrine Paindavoine, Valérie Kubiniek, Virginie Perrin, Bérengère Dadone-Montaudié, TIRODE, Franck, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNICANCER, Université de Bordeaux (UB), Université Nice Sophia Antipolis (... - 2019) (UNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Lyon (CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux, and Institut Bergonié - CRLCC Bordeaux
Subjects: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Skin Neoplasms, Oncogene Proteins, Fusion, Chromosomal translocation, PDGFRB, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, CDKN2A, Pathognomonic, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Dermatofibrosarcoma protuberans, Humans, Aged, Gene Rearrangement, Platelet-Derived Growth Factor, Lymphokines, PDGFB, medicine.diagnostic_test, Dermatofibrosarcoma, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Gene rearrangement, Proto-Oncogene Proteins c-sis, Middle Aged, medicine.disease, Collagen Type I, alpha 1 Chain, 030104 developmental biology, 030220 oncology & carcinogenesis, Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Fluorescence in situ hybridization
Abstract: International audience; Dermatofibrosarcoma protuberans is underlined by recurrent collagen type I alpha 1 chain-platelet-derived growth factor B chain (COL1A1-PDGFB) fusions but ~ 4% of typical dermatofibrosarcoma protuberans remain negative for this translocation in routine molecular screening. We investigated a series of 21 cases not associated with the pathognomonic COL1A1-PDGFB fusion on routine fluorescence in situ hybridization (FISH) testing. All cases displayed morphological and clinical features consistent with the diagnosis of dermatofibrosarcoma protuberans. RNA-sequencing analysis was successful in 20 cases. The classical COL1A1-PDGFB fusion was present in 40% of cases (n = 8/20), and subsequently confirmed with a COL1A1 break-apart FISH probe in all but one case (n = 7/8). 55% of cases (n = 11/20) displayed novel PDGFD rearrangements; PDGFD being fused either to the 5' part of COL6A3 (2q37.3) (n = 9/11) or EMILIN2 (18p11) (n = 2/11). All rearrangements led to in-frame fusion transcripts and were confirmed at genomic level by FISH and/or array-comparative genomic hybridization. PDGFD-rearranged dermatofibrosarcoma protuberans presented clinical outcomes similar to typical dermatofibrosarcoma protuberans. Notably, the two EMILIN2-PDGFD cases displayed fibrosarcomatous transformation and homozygous deletions of CDKN2A at genomic level. We report the first recurrent molecular variant of dermatofibrosarcoma protuberans involving PDGFD, which functionally mimic bona fide COL1A1-PDGFB fusions, leading presumably to a similar autocrine loop-stimulating PDGFRB. This study also emphasizes that COL1A1-PDGFB fusions can be cytogenetically cryptic on FISH testing in a subset of cases, thereby representing a diagnostic pitfall that pathologists should be aware of.
Published: 2018
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18. Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response

Author: Christina D. Drenberg, Kirsten M. Johnson, Franck Tirode, Sunil Sharma, Ioana L. Pop, Ranajeet S. Saund, Kathleen I. Pishas, David F. Callen, Brian D. Crompton, Elizabeth R. Lawlor, Cenny Taslim, Mary C. Beckerle, Stephen L. Lessnick, Emily R. Theisen, Olivier Delattre, Jaume Mora, TIRODE, Franck, Cancer Therapeutics Laboratory [Adelaide, SA, Australia], Center for Childhood Cancer and Blood Disorders [Colombus, OH, USA], Division of Pharmaceutics, College of Pharmacy, Ohio State University [Columbus] (OSU), Comprehensive Cancer Center [Colombus], Huntsman Cancer Institute [Salt Lake City], University of Utah, Department of Pediatric Oncology [Boston, MA, USA], Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Department of Pediatrics and Communicable Diseases [Ann Arbor, MI, USA], Department of Pathology [Ann Arbor, MI, USA] (Medical School), University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatric Oncology [Barcelona, Spain], Hospital Sant Joan de Déu [Barcelona], Unité de Génétique Somatique [Institut Curie, Paris], Institut Curie [Paris], TGen Clinical Sciences [Phoenix, AZ, USA], Division of Pediatric Hematology/ Oncology/BMT [Columbus, OH, USA], Abigail Wexner Research Institute, Nationwide Children's Hospital-Nationwide Children's Hospital, and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Cancer Research, Adolescent, GSK-LSD1, Apoptosis, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, Small Molecule Libraries, 03 medical and health sciences, ETS1, [SDV.CAN] Life Sciences [q-bio]/Cancer, CDKN2A, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Enzyme Inhibitors, Child, SP-2509, Regulation of gene expression, Histone Demethylases, Endoplasmic reticulum, KDM1A, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Endoplasmic Reticulum Stress, 3. Good health, Gene Expression Regulation, Neoplastic, Endoplasmic reticulum stress response, 030104 developmental biology, Oncology, KDM1A/LSD1, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA Interference, Sarcoma, Carcinogenesis, Ewing sarcoma, Signal Transduction
Abstract: Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n = 17; IC50 range, 81 –1,593 nmol/L), in contrast resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50 > 300 μmol/L). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Mol Cancer Ther; 17(9); 1902–16. ©2018 AACR.
Published: 2018
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19. BAFfling pathologies: Alterations of BAF complexes in cancer

Author: François Le Loarer, Franck Tirode, Ophélie Arnaud, TIRODE, Franck, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Centre Léon Bérard, the Cancer Research Center of Lyon, the Cancéropôle Ile de France and the Institut National du Cancer (grant INCa-PLBIO16-208)., and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Cancer Research, Chromosomal Proteins, Non-Histone, Protein subunit, cells, genetic processes, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Biology, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neoplasms, medicine, Nucleosome, Animals, Humans, SMARCB1, BAF complex, Transcription factor, Gene, Mutation, SWI/SNF complex, SWI/SNF-deficient pathology, Nuclear Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, SMARCB1 Protein, Chromatin Assembly and Disassembly, 3. Good health, Cell biology, Chromatin, Nucleosomes, DNA-Binding Proteins, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Oncology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], BAF-deficient pathology, biological phenomena, cell phenomena, and immunity, Transcription Factors
Abstract: International audience; To activate or repress specific genes, chromatin is constantly modified by chromatin-remodeling complexes. Among these complexes, the SWItch/Sucrose Non-Fermenting (SWI/SNF) complex, also referred to as BRG1-Associated Factor (BAF) complex, moves the nucleosome along chromatin using energy provided by ATP hydrolysis. In mammalian organisms, the SWI/SNF complex is composed of 10-15 subunits, depending on cell type, and a defect in one of these subunits can have dramatic consequences. In this review we will focus on the alterations identified in the SWI/SNF (BAF) complex subunits that lead to cancerous pathologies. While SMARCB1 was the first mutated subunit to be reported in a majority of malignant rhabdoid tumors, the advent of next-generation sequencing allowed the discovery of mutations in various SWI/SNF subunits within a broad spectrum of cancers. In most cases, the mutation leads to a loss of expression or to a truncated subunit unable to perform its function. Even though it is now commonly acknowledged that approximately 20% of all cancers present a mutation in a SWI/SNF subunit, some cancers are associated to a specific alteration of a SWI/SNF subunit, which acts either as tumor suppressor genes or as oncogenes, and therefore constitute diagnostic or prognostic biomarkers. Consistently, therapeutic strategies targeting SWI/SNF subunits or the genes affected downstream have been revealed to treat cancers.
Published: 2017
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20. ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions

Author: Sophie Le Guellec, Sarah Watson, Franck Tirode, Jean-Michel Coindre, Gaëlle Pérot, Valérie Velasco, Institut Claudius Regaud, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Institut Bergonié [Bordeaux], UNICANCER, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and TIRODE, Franck
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Pathology, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Pathology and Forensic Medicine, Diagnosis, Differential, Surgical pathology, Sarcoma, Synovial, Young Adult, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Proto-Oncogene Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, medicine, Humans, Child, Rhabdomyosarcoma, Rhabdoid Tumor, Rhabdomyosarcoma, Alveolar, Aged, Aged, 80 and over, Proto-Oncogene Proteins c-ets, Soft tissue sarcoma, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Gene rearrangement, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, 3. Good health, Repressor Proteins, 030104 developmental biology, Cytopathology, 030220 oncology & carcinogenesis, Sarcoma, Small Cell, Alveolar rhabdomyosarcoma, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Adenovirus E1A Proteins, Sarcoma, Hematopathology
Abstract: International audience; Subsets of primitive round-cell sarcomas remain difficult to diagnose and classify. Among these is a rare round-cell sarcoma that harbors a CIC gene rearrangement known as CIC-rearranged undifferentiated round-cell sarcoma, which is most commonly fused to the DUX4 gene. Owing to its aggressive clinical behavior and potential therapeutic implications, accurate identification of this novel soft tissue sarcoma is necessary. Definitive diagnosis requires molecular confirmation, but only a few centers are as yet able to perform this test. Several studies have shown that PEA3 subfamily genes, notably ETV4 (belonging to the family of ETS transcription factors), are upregulated in CIC-rearranged undifferentiated round-cell sarcomas. We performed a detailed immunohistochemical analysis to investigate ETV4 expression in CIC-rearranged undifferentiated round-cell sarcomas and their potential mimics (especially Ewing sarcomas). The study cohort included 17 cases of CIC-rearranged undifferentiated round-cell sarcomas, and 110 tumors that morphologically mimic CIC-rearranged undifferentiated round-cell sarcomas: 43 Ewing sarcomas, 25 alveolar rhabdomyosarcomas, 20 poorly differentiated round-cell synovial sarcomas, 10 desmoplastic round-cell tumors, 5 BCOR-CCNB3 sarcomas, 5 lymphoblastic lymphomas, and 2 rhabdoid tumors. All CIC-rearranged undifferentiated round-cell sarcomas (on core needle biopsies and open biopsies) were ETV4-positive with a strong diffuse nuclear pattern. Among the other 110 tumors, only six cases (four Ewing sarcomas, one alveolar rhabdomyosarcoma, and one desmoplastic round-cell tumor) showed focal (o5% of tumor cells) and very weak nuclear expression of ETV4; all other tumors were completely negative for ETV4. We conclude that systematic immunohistochemical analysis of ETV4 makes it possible to diagnose undifferentiated round-cell sarcomas (with no molecular markers for sarcoma-associated translocation) such as CIC-rearranged undifferentiated round-cell sarcoma.
Published: 2016
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21. Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model

Author: Jan Tuckermann, Franck Tirode, Michelle Marques Howarth, Tsion Z. Minas, Takuro Nakamura, Olivier Delattre, Lukas Kenner, Jeffrey A. Toretsky, Miwa Tanaka, Tahereh Javaheri, Jenny Han, E. Alejandro Sweet-Cordero, Barbara E. Kream, Barbara Sax, Sean Lee, Haydar Çelik, Aykut Üren, Heinrich Kovar, Hong-Jun Kang, Richard Moriggl, Sung-Hyeok Hong, Zhi-Yan Han, Didier Surdez, Department of Oncology [Washington, DC, USA], Georgetown University School of Medicine [Washington, DC USA], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Ludwig Boltzmann Institute for Cancer Research [Vienna, Austria], Division of Carcinogenesis [Tokyo, Japan], The Cancer Institute [Tokyo, Japan]-Japanese Foundation for Cancer Research [Tokyo, Japan], Division of Hematology and Oncology [Stanford, CA, USA] (Department of Pediatrics), Stanford University, Department of Pathology and Laboratory Medicine [New Orleans, LA, USA], Department of Medicine, and Genetics and Genome Sciences [Farmington, CT, USA], Institute of Comparative Molecular Endocrinology [Ulm, Germany], Clinical Institute of Pathology [Vienna, Austria], Department of Pathology of Laboratory Animals [Vienna, Austria] (UPLA), Children’s Cancer Research Institute [Vienna, Austria], Department of Pediatrics [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Institute of Animal Breeding and Genetics [Vienna, Austria] (Department for Biomedical Sciences), University of Veterinary Medicine [Vienna] (Vetmeduni), Unité de Génétique Somatique [Institut Curie, Paris], Institut Curie [Paris], TIRODE, Franck, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Universität Ulm - Ulm University [Ulm, Allemagne]
Subjects: 0301 basic medicine, Gerontology, Proto-Oncogene Protein c-fli-1, Oncogene Proteins, Fusion, Chromosomal translocation, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, Transgenic, Mice, EWS-FLI1 driven transgenic mouse model, Gene Knock-In Techniques, Promoter Regions, Genetic, Oncogene Proteins, Tumor, Sarcoma, Gene Expression Regulation, Neoplastic, Oncology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Research Paper, Genetically modified mouse, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, SOX9, Sarcoma, Ewing, Cell Line, Adenoviridae, Promoter Regions, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetic, Ewing, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, Fusion, EWS-FLI1, Neoplastic, Animal, business.industry, fungi, Promoter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Embryonic stem cell, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Disease Models, Cancer research, RNA-Binding Protein EWS, business, Neoplasm Transplantation, Ewing sarcoma
Abstract: International audience; Ewing sarcoma (ES) involves a tumor-specific chromosomal translocation that produces the EWS-FLI1 protein, which is required for the growth of ES cells both in vitro and in vivo. However, an EWS-FLI1-driven transgenic mouse model is not currently available. Here, we present data from six independent laboratories seeking an alternative approach to express EWS-FLI1 in different murine tissues. We used the Runx2, Col1a2.3, Col1a3.6, Prx1, CAG, Nse, NEFL, Dermo1, P0, Sox9 and Osterix promoters to target EWS-FLI1 or Cre expression. Additional approaches included the induction of an endogenous chromosomal translocation, in utero knock-in, and the injection of Cre-expressing adenovirus to induce EWS-FLI1 expression locally in multiple lineages. Most models resulted in embryonic lethality or developmental defects. EWS-FLI1-induced apoptosis, promoter leakiness, the lack of potential cofactors, and the difficulty of expressing EWS-FLI1 in specific sites were considered the primary reasons for the failed attempts to create a transgenic mouse model of ES.
Published: 2016
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22. Oncostatin M Is a Growth Factor for Ewing Sarcoma

Author: Pierre J. Guihard, Marie F. Heymann, Franck Tirode, Frédéric Blanchard, Karine Laud, Olivier Delattre, Emmanuelle David, Marc Baud'huin, Françoise Rédini, Dominique Heymann, Centre de recherche sur l'action politique de l'UNIL (CRAPUL), Université de Lausanne (UNIL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Equipe LIGUE Nationale Contre le Cancer 2012, Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Centre de Recherche en Sciences et Technologies de l'Information et de la Communication - EA 3804 (CRESTIC), Université de Reims Champagne-Ardenne (URCA), TIRODE, Franck, Université de Lausanne = University of Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Oncogene Proteins, Fusion, Cellular differentiation, medicine.medical_treatment, Leukemia inhibitory factor receptor, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Leukemia Inhibitory Factor, Mesoderm, Mice, 0302 clinical medicine, Cytokine Receptor gp130, Osteosarcoma, 0303 health sciences, Oncostatin M, Cell Differentiation, 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], STAT3 Transcription Factor, Receptors, OSM-LIF, Chondrosarcoma, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, Models, Biological, Pathology and Forensic Medicine, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neuroblastoma, medicine, Animals, Humans, Cell Proliferation, 030304 developmental biology, Proto-Oncogene Protein c-fli-1, Growth factor, fungi, Mesenchymal stem cell, Receptors, Oncostatin M, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Protein Subunits, biology.protein, Cancer research, RNA-Binding Protein EWS, Leukemia inhibitory factor
Abstract: International audience; Primary bone tumors, osteosarcomas and chondrosarcomas, derive from mesenchymal stem cells committed into osteoblasts and chondrocytes; in Ewing sarcomas (ESs), the oncogenic fusion protein EWS-FLI1 prevents mesenchymal differentiation and induces neuroectodermic features. Oncostatin M (OSM) is a cytokine from the IL-6 family that modulates proliferation and differentiation in numerous cells. The basis for inhibition versus induction of proliferation by this cytokine is obscure, although MYC was described as a potent molecular switch in OSM signaling. We show herein that, in contrast to osteosarcomas and chondrosarcomas, for which OSM was cytostatic, OSM induced proliferation of ES cell lines. Knockdown experiments demonstrated that growth induction by OSM depends on both types I [leukemia inhibitory factor receptor (LIFR)] and II [OSM receptor (OSMR)] receptors, high STAT3 activation, and induction of MYC to a high expression level. Indeed, ES cell lines, mice xenografts, and patient biopsy specimens poorly expressed LIF, precluding LIFR lysosomal degradation and OSMR transcriptional induction, thus leading to a high LIFR/OSMR ratio. Because other neuroectodermic tumors (ie, glioma, medulloblastoma, and neuroblastoma) had a similar expression profile, the main role of EWS-FLI1 could be through maintenance of sternness and neuroectodermic features, characterized by a low LW, a high LIFR/OSMR ratio, and high MYC expression. Thus, this study on rare bone malignancies gives valuable insights on more common cancer regulatory mechanisms and could provide new therapeutic opportunities.
Published: 2012
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23. A Role for the TFIIH XPB DNA Helicase in Promoter Escape by RNA Polymerase II

Author: Jean-Marc Egly, Rodney J. Moreland, Ronald C. Conaway, Joan W. Conaway, Franck Tirode, Qin Yan, TIRODE, Franck, Oklahoma Medical Research Foundation (OMRF), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and This work was supported in part by National Institutes of Health Grant GM41628 (to R. C. C.), a Human Frontier Grant (to J. M. E.), and by funds provided to the Oklahoma Medical Research Foundation by the H. A. and Mary K. Chapman Charitable Trust.
Subjects: Transcription, Genetic, [SDV.CAN]Life Sciences [q-bio]/Cancer, RNA polymerase II, Protein Serine-Threonine Kinases, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, Transcription Factors, TFII, 03 medical and health sciences, Adenosine Triphosphate, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Promoter Regions, Genetic, Molecular Biology, RNA polymerase II holoenzyme, 030304 developmental biology, 0303 health sciences, biology, DNA Helicases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Molecular biology, RNA Helicase A, Cyclin-Dependent Kinases, DNA-Binding Proteins, Transcription Factor TFIIH, Mutation, biology.protein, Transcription factor II H, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA Polymerase II, Transcription factor II D, Transcription factor II B, Cyclin-Dependent Kinase-Activating Kinase, 030217 neurology & neurosurgery, Transcription factor II A, Transcription Factors
Abstract: International audience; TFIIH is an RNA polymerase II transcription factor that performs ATP-dependent functions in both transcription initiation, where it catalyzes formation of the open complex, and in promoter escape, where it suppresses arrest of the early elongation complex at promoter -proximal sites. TFIIH possesses three known ATP-dependent activities: a 3 3 5 DNA helicase catalyzed by its XPB subunit, a 5 3 3 DNA helicase catalyzed by its XPD subunit, and a carboxyl-terminal domain (CTD) ki-nase activity catalyzed by its CDK7 subunit. In this report , we exploit TFIIH mutants to investigate the contributions of TFIIH DNA helicase and CTD kinase activities to efficient promoter escape by RNA polymer-ase II in a minimal transcription system reconstituted with purified polymerase and general initiation factors. Our findings argue that the TFIIH XPB DNA helicase is primarily responsible for preventing premature arrest of early elongation intermediates during exit of polymerase from the promoter.
Published: 1999
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24. Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis

Author: Gautier Stoll, Andrei Zinovyev, Didier Surdez, Franck Tirode, Olivier Delattre, Emmanuel Barillot, Karine Laud, Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut National de la Santé et de la Recherche Médicale, Institut Curie, Agence National de la Recherche [SITCONproject: NR-06-BYOS-0004], Institut National du Cancer[SYBEwing project: 2009-1-PLBIO-04], Ligue Nationalecontre le Cancer (Equipe labellisée and CIT program), Réseau National des Génopoles, European Union(APOSYS, KCK and EET pipeline projects), sociétéFrançaise des Cancers de l’Enfant and the following associations: Courir pour Mathieu, Dans les pas du Géant,Olivier Chape, Les Bagouzamanon and les Amis deClaire. The research leading to these results has receivedfunding from the European Union Seventh FrameworkProgramme (FP7/2007-2013) ASSET project [FP7-HEALTH-2010-259348]., European Project: 259348,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,ASSET(2010), MINES ParisTech - École nationale supérieure des mines de Paris, TIRODE, Franck, and ASSET: Analysing and Striking the Sensitivities of Embryonal Tumours - ASSET - - EC:FP7:HEALTH2010-11-01 - 2016-04-30 - 259348 - VALID
Subjects: Oncogene Proteins, Fusion, Systems biology, Gene regulatory network, Apoptosis, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Data Mining, Humans, Gene silencing, Gene Regulatory Networks, RNA, Small Interfering, Transcription factor, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Models, Genetic, Proto-Oncogene Protein c-fli-1, Systems Biology, fungi, Computational Biology, Ewing's sarcoma, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell cycle, medicine.disease, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA-Binding Protein EWS, Signal Transduction
Abstract: International audience; Ewing sarcoma is the second most frequent pediat-ric bone tumor. In most of the patients, a chromo-somal translocation leads to the expression of the EWS-FLI1 chimeric transcription factor that is the major oncogene in this pathology. Relative genetic simplicity of Ewing sarcoma makes it particularly attractive for studying cancer in a systemic manner. Silencing EWS-FLI1 induces cell cycle alteration and ultimately leads to apoptosis, but the exact molecular mechanisms underlying this phenotype are unclear. In this study, a network linking EWS-FLI1 to cell cycle and apoptosis phenotypes was constructed through an original method of network reconstruction. Transcriptome time-series after EWS-FLI1 silencing were used to identify core modulated genes by an original scoring method based on fitting expression profile dynamics curves. Literature data mining was then used to connect these modulated genes into a network. The validity of a subpart of this network was assessed by siRNA/RT-QPCR experiments on four additional Ewing cell lines and confirmed most of the links. Based on the network and the transcriptome data, CUL1 was identified as a new potential target of EWS-FLI1. Altogether, using an original methodology of data integration, we provide the first version of EWS-FLI1 network model of cell cycle and apoptosis regulation.
Published: 2013
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25. Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL

Author: Dominique Heymann, Valérie Trichet, Franck Tirode, Francois Lamoureux, Françoise Rédini, Bruno Pitard, Marie-Françoise Heymann, Gaelle Picarda, Etienne Matous, Jérôme Amiaud, Céline Charrier, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe LIGUE Nationale Contre le Cancer 2012, Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Service d’Anatomopathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by a grant from Novartis Pharma (Rueil-Malmaison, France), by the 'Fédération Nationale Enfants et Santé', the 'Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l’Adolescent' and the 'Institut National du Cancer' (Grant number R09018NN)., Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), TIRODE, Franck, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: musculoskeletal diseases, Pathology, medicine.medical_specialty, Bone resorption, TRAIL, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Bone remodeling, 03 medical and health sciences, 0302 clinical medicine, Osteoprotegerin, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, biology, business.industry, RANKL, Ewing's sarcoma, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, 3. Good health, Resorption, Oncology, 030220 oncology & carcinogenesis, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Sarcoma, business, Research Article
Abstract: International audience; Ewing's sarcoma (ES) associated with high osyeolytic lesions typically arises in the bones of children and adolescents. The development of multidisciplinary therapy has increased current long-term survival rates to greater than 50% but only 20% for high risk group patients (relapse, metastases, etc.). Among new therapeutic approaches, osteoprotegerin (OPG), an anti-bone resorption molecule may represent a promising candidate to inhibit RANKL-mediated osteolytic component of ES and consequently to limit the tumor development. Xenogenic orthotopic models of Ewing's sarcoma were induced by intra-osseous injection of human TC-71 ES cells. OPG was administered in vivo by non-viral gene transfer using an amphiphilic non ionic block copolymer. ES bearing mice were assigned to controls (no treatment, synthetic vector alone or F68/ empty pcDNA3.1 plasmid) and hOPG treated groups. A substantial but not significant inhibition of tumor development was observed in the hOPG group as compared to control groups. Marked bone lesions were revealed by micro-computed tomography analyses in control groups whereas a normal bone micro-architecture was preserved in the hOPG treated group. RANKL over-expressed in ES animal model was expressed by tumor cells rather than by host cells. However, TRAIL present in the tumor microenviron-ment may interfere with OPG effect on tumor development and bone remodeling via RANKL inhibition. In conclusion, the use of a xenogenic model of Ewing's sarcoma allowed discriminating between the tumor and host cells responsible for the elevation of RANKL production observed in this tumor and demonstrated the relevance of blocking RANKL by OPG as a promising therapy in ES.
Published: 2013
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26. Targeting the EWSR1-FLI1 Oncogene-Induced Protein Kinase PKC- Abolishes Ewing Sarcoma Growth in vivo

Author: Françoise Rédini, Virginie Perrin, Birgit Geoerger, Didier Surdez, Anne-Valérie Decouvelaere, Franck Tirode, Olivier Delattre, Gonzague de Pinieux, Zhi-Yan Han, Gaëlle Pierron, Estelle Daudigeos-Dubus, Stelly Ballet, Magdalena Benetkiewicz, Francois Lamoureux, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut Curie [Paris], Unité de Génétique Somatique, Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), This work was supported by grants from the Institut National de la Santé et de la RechercheMédicale (FL,FR,OD,FT), the Centre National de la Recherche Scientifique (EDD,BG), theInstitut Curie (DS,MB,VP,ZHY,GP,SB), the Institut National du Cancer (DS :SYBEwingproject: 2009-1-PLBIO-04 and FT,VP :BORTES project : 2008-PLBIO-06), the LigueNationale contre le Cancer (Equipe labellisée and CIT program), the Réseau National desGénopoles, Agence National de la Recherche, the European Union (MB : KCK and EETpipeline programs), the société Française des Cancers de l’Enfant, and the followingassociations: Courir pour Mathieu, Dans les pas du Géant, Olivier Chape, LesBagouzamanon and les Amis de Claire., TIRODE, Franck, and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Cancer Research, Oncogene Proteins, Fusion, Oncogene Proteins, Protein Kinase C beta, Mice, SCID, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Histones, Mice, 0302 clinical medicine, Protein Kinase B, Phosphorylation, Protein Kinase C, Regulation of gene expression, 0303 health sciences, apoptosis, RNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, FLI1, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, RNA Interference, Signal transduction, Cell Survival, EWSR1-FLI1, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, Gene silencing, Gene Silencing, xenograft, Protein kinase C, 030304 developmental biology, Oncogene, Proto-Oncogene Protein c-fli-1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cancer research, Calmodulin-Binding Proteins, RNA-Binding Protein EWS, Ewing sarcoma
Abstract: International audience; Identification of druggable targets is a prerequisite for developing targeted therapies againstEwing sarcoma. We report the identification of Protein Kinase C Beta (PRKCB) as a proteinspecifically and highly expressed in Ewing sarcoma as compared to other pediatric cancers.Its transcriptional activation is directly regulated by the EWSR1-FLI1 oncogene. Gettinginsights in PRKCB activity we show that, together with PRKCA, it is responsible for thephosphorylation of histone H3T6, allowing global maintenance of H3K4 trimethylation on avariety of gene promoters. In the long term, PRKCB RNA interference induces apoptosis invitro. More importantly, in xenograft mice models, complete impairment of tumor engraftmentand even tumor regression were observed upon PRKCB inhibition, highlighting PRKCB as amost valuable therapeutic target. Deciphering PRKCB roles in Ewing sarcoma usingexpression profiling, we found a strong overlap with genes modulated by EWSR1-FLI1 andan involvement of RPKCB in regulating crucial signaling pathways. Altogether, we show thatPRKCB may have two important independent functions and should be considered as highlyvaluable for understanding Ewing sarcoma biology and as a promising target for newtherapeutic approaches in Ewing sarcoma.
Published: 2012
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27. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion

Author: Carlo Lucchesi, Olivier Delattre, Stelly Ballet, Gaëlle Pierron, Sarah Cohen-Gogo, Stéphanie Reynaud, Jean-Michel Coindre, Franck Tirode, Virginie Perrin, Unité de Génétique Somatique [Institut Curie, Paris], Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut Bergonié [Bordeaux], UNICANCER, This work was supported by grants from the Ligue Nationale Contre le Cancer (Equipe labellisée and CIT program), the Région Ile de France, the INCa (n°2008-044, 0627 and ZP09-027-EPI), the European Union (EET pipeline), and the following associations: Courir pour Mathieu, Dans les pas du Géant, Olivier Chape, Les Bagouzamanon and les Amis de Claire., and TIRODE, Franck
Subjects: Male, Oncogene Proteins, Fusion, Chromosomal translocation, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Translocation, Genetic, Fusion gene, Mice, 0302 clinical medicine, Child, X chromosome, Genetics, Osteosarcoma, 0303 health sciences, Sarcoma, BCL6, 3. Good health, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Gene Fusion, Adult, Adolescent, Molecular Sequence Data, CD99, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Cyclin B, Bone Sarcoma, Biology, Undifferentiated Round Cell Sarcoma, Cell Line, Young Adult, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Proto-Oncogene Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, medicine, Animals, Humans, 030304 developmental biology, Chromosomes, Human, X, Base Sequence, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sequence Analysis, DNA, medicine.disease, Repressor Proteins, NIH 3T3 Cells, Cancer research, RNA-Binding Protein EWS
Abstract: Comment in [Birth notice: a new bone sarcoma has been born]. [Bull Cancer. 2012]; International audience; The identification of subtype-specific translocations has revolutionized the diagnostics of sarcoma and has provided new insight into oncogenesis. We used RNA-seq to investigate samples from individuals diagnosed with small round cell tumors of bone, possibly Ewing sarcoma, but which lacked the canonical EWSR1-ETS translocation. A new fusion was observed between BCOR (encoding the BCL6 co-repressor) and CCNB3 (encoding the testis-specific cyclin B3) on the X chromosome. RNA-seq results were confirmed by RT-PCR and through cloning of the tumor-specific genomic translocation breakpoints. In total, 24 BCOR-CCNB3-positive tumors were identified among a series of 594 sarcoma cases. Gene profiling experiments indicated that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this subgroup of sarcoma and that overexpression of BCOR-CCNB3 or of truncated CCNB3 activates S phase in NIH3T3 cells. Thus, the intrachromosomal X-chromosome fusion described here represents a new subtype of bone sarcoma caused by a newly identified gene fusion mechanism.
Published: 2012
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28. The first European interdisciplinary ewing sarcoma research summit

Author: Jozef Ban, Enrique de Alava, Pierre Åman, Stephen L. Lessnick, Dave N. T. Aryee, Stefan Burdach, Udo Kontny, Stephan Niedan, Jeffrey A. Toretsky, Simone Fulda, Lee J. Helman, Raphaela Schwentner, Selena Ventura, Angelika Eggert, Françoise Rédini, Antonio Llombart-Bosch, Markus Metzler, Poul H. Sorensen, Beat W. Schäfer, Heinrich Kovar, Argyro Fourtouna, Katia Scotlandi, Gunther Richter, Sue A. Burchill, Uta Dirksen, Olivier Delattre, Richard Moriggl, Elizabeth R. Lawlor, David Herrero-Martin, Javier Alonso, Martin S. Staege, Lucia T. Riedmann, Pancras C.W. Hogendoorn, Franck Tirode, Ruth Ladenstein, Claudia Rossig, Jenny Potratz, Children’s Cancer Research Institute [Vienna, Austria], Department of Pediatrics [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Sahlgrenska Academy at University of Gothenburg [Göteborg], Leeds Institute of Molecular Medicine, University of Leeds, Children’s Cancer Research Center and Department of Pediatrics [Munich, Germany], Technical University and Comprehensive Cancer Center Munich - CCCM [Germany]-Klinikum rechts der Isar [Munich, Germany], University Hospital of Salamanca, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Universitätsklinikum Münster [Munster, Germany], Goethe-University, Goethe-Universität Frankfurt am Main, Center for Cancer Rearch [Bethesda, MA, USA], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Leiden University Medical Center (LUMC), University Children's Hospital [Freiburg, Germany], Department of Pediatrics and Department of Pathology [Ann Arbor, MI, USA], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Pathology [Ann Arbor, MI, USA] (Medical School), Huntsman Cancer Institute [Salt Lake City], University of Utah, University of Valencia, Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen [Germany], Ludwig Boltzmann Institute for Cancer Research [Vienna, Austria], Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Oncology and Children’s Research Center [Zurich, Switzerland], University Children’s Hospital Zurich, CRS Development of Biomolecular Therapies [Bologna, Italy] (Experimental Oncology Lab), University of Bologna-The Rizzoli Institute [Bologna, Italy], Department of Molecular Oncology [British Columbia, Canada], British Columbia Cancer Research Centre [British Columbia, Canada], Children's Cancer Research Center [Halle, Germany], Georgetown Lombardi Comprehensive Cancer Center, University Children's Hospital of Essen, Klinikum rechts der Isar [Munich, Germany]-Technical University and Comprehensive Cancer Center Munich - CCCM [Germany], TIRODE, Franck, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), University Hospital Erlangen = Uniklinikum Erlangen, University of Bologna/Università di Bologna-The Rizzoli Institute [Bologna, Italy], and Widemann, BC
Subjects: Epigenomics, Cancer Research, Alternative medicine, Medizin, ComputingMilieux_LEGALASPECTSOFCOMPUTING, Review Article, Bioinformatics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, drug screen, 0302 clinical medicine, Drug screen, Cancer genomics, signalling, Sarcomagenesis, 0303 health sciences, sarcomagenesis, Summit, geography.geographical_feature_category, Opinion leadership, Genomics, Laboratory results, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, animal models, 3. Good health, Animal models, Metastatic Ewing Sarcoma, Oncology, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Epigenetics, Sarcoma, Immunotherapy, Prioritization, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, genomics, 030304 developmental biology, Medical education, geography, epigenetics, business.industry, biomarkers, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Clinical trial, prognosis, business, Biomarkers, Ewing sarcoma
Abstract: This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License.-- et al., The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials.
Published: 2012
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29. Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Author: Javier Alonso, Philippe Froguel, David G. Cox, Ana Patiño-García, Jean Michon, Sophie Postel-Vinay, Gaëlle Pierron, Olivier Delattre, Franck Tirode, Anna González-Neira, Stelly Ballet, Piero Picci, Françoise Clavel-Chapelon, Christian Dina, Odile Oberlin, Stephen J. Chanock, Carlo Lucchesi, Brigitte Bressac-de Paillerets, Karine Laud, François Doz, Gilles Thomas, Stéphanie Reynaud, Udo Kontny, Heinrich Kovar, Eve Lapouble, Amelie S. Veron, Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut Curie [Paris], Centre Scientifique de Monaco (CSM), Children’s Cancer Research Institute [Vienna, Austria], Département de Pédiatrie, Systèmes d'élevage, nutrition animale et humaine (SENAH), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin [Freiburg, Germany], Genotyping Unit (CeGen), Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Istituto Ortopedico Rizzoli [Bologna, Italy], Instituto de Estudios Fiscales, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département d'oncologie pédiatrique, Département de Pédiatrie Adolescents et Jeunes Adultes [Institut Curie], Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Epidemiology and Biostatistics, Imperial College London-Faculty of Medicine-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), This work was supported by grants from the Institut Curie, the Inserm, the Ligue Nationale Contre le Cancer (Equipe labellisée, Carte d’Identité des Tumeurs program and Recherche Epidémiologique 2009 program), the Région Ile de France, the Institut National du Cancer (2008-044, 0627 and ZP09-027- EPI), the Synergie Lyon Cancer foundation, the KCK and European Embryonal Tumor (EET) pipeline programs, the Société Française des Cancers de l’Enfant, the Spanish Ministry of Science and Technology (SAF2009-10158), the Fundación de la Asociación Española Contra el Cáncer, the Fundación María Francisca de Roviralta and the Sociedad Española de Hematología y Oncología Pediátricas and the following associations: Courir pour Mathieu, Dans les pas du Géant, Olivier Chape, Les Bagouzamanon, Enfants et Santé and les Amis de Claire., Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), TIRODE, Franck, Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie, Musee oceanographique de Monaco, AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: Genotype, Genome-wide association study, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sarcoma ewing, TARDBP, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Polymorphism (computer science), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Early Growth Response Protein 2, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 10, Cancer, Pediatric Tumor, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, 3. Good health, DNA-Binding Proteins, Logistic Models, Haplotypes, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Sarcoma, France, Genome-Wide Association Study
Abstract: International audience; Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.
Published: 2012
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30. Antagonism pattern detection between microRNA and target expression in Ewing's sarcoma

Author: Franck Tirode, Karine Laud-Duval, Stéphanie Reynaud, Andrei Zinovyev, Gaëlle Pierron, Loredana Martignetti, Olivier Delattre, Emmanuel Barillot, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biologie tumorale [Institut Curie, Paris], Institut Curie [Paris], The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n.259348. This work was supported by the Institut National du Cancer (SybEwing project) and by the Carte d’Identite des Tumeurs/Program of the Ligue Nationale Contre le Cancer. LM, AZ and EB are members of the team ‘‘Computational Systems Biology of Cancer,’’ Equipe labellisee by the Ligue Nationale Contre le Cancer. KL, FT and OD are members of the team ‘‘Genetics and biology of childhood cancers and of sporadic breast cancers,’’ Equipe labellisee by the Ligue Nationale Contre le Cancer., European Project: 259348,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,ASSET(2010), Mines Paris - PSL (École nationale supérieure des mines de Paris), TIRODE, Franck, and ASSET: Analysing and Striking the Sensitivities of Embryonal Tumours - ASSET - - EC:FP7:HEALTH2010-11-01 - 2016-04-30 - 259348 - VALID
Subjects: Gene Expression, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, Pattern Recognition, Automated, Transcriptomes, Transcriptome, 0302 clinical medicine, RNA interference, Gene expression, Molecular Cell Biology, Bone and Soft Tissue Sarcomas, Basic Cancer Research, Genetics, 0303 health sciences, Multidisciplinary, Genomics, Nucleic acids, Oncology, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, Research Article, Science, Ewing Sarcoma, Context (language use), MiRNA binding, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, Molecular Genetics, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genome Analysis Tools, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, medicine, Gene silencing, Humans, RNA, Messenger, 030304 developmental biology, Regulatory Networks, Messenger RNA, Ewing's sarcoma, Computational Biology, Reproducibility of Results, Cancers and Neoplasms, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MicroRNAs, RNA, Genome Expression Analysis
Abstract: International audience; MicroRNAs (miRNAs) have emerged as fundamental regulators that silence gene expression at the post-transcriptional and translational levels. The identification of their targets is a major challenge to elucidate the regulated biological processes. The overall effect of miRNA is reflected on target mRNA expression, suggesting the design of new investigative methods based on high-throughput experimental data such as miRNA and transcriptome profiles. We propose a novel statistical measure of non-linear dependence between miRNA and mRNA expression, in order to infer miRNA-target interactions. This approach, which we name antagonism pattern detection, is based on the statistical recognition of a triangular-shaped pattern in miRNA-target expression profiles. This pattern is observed in miRNA-target expression measurements since their simultaneously elevated expression is statistically under-represented in the case of miRNA silencing effect. The proposed method enables miRNA target prediction to strongly rely on cellular context and physiological conditions reflected by expression data. The procedure has been assessed on synthetic datasets and tested on a set of real positive controls. Then it has been applied to analyze expression data from Ewing's sarcoma patients. The antagonism relationship is evaluated as a good indicator of real miRNA-target biological interaction. The predicted targets are consistently enriched for miRNA binding site motifs in their 39UTR. Moreover, we reveal sets of predicted targets for each miRNA sharing important biological function. The procedure allows us to infer crucial miRNA regulators and their potential targets in Ewing's sarcoma disease. It can be considered as a valid statistical approach to discover new insights in the miRNA regulatory mechanisms.
Published: 2012
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31. A functional, new short isoform of death receptor 4 in Ewing's sarcoma cell lines may be involved in TRAIL sensitivity/resistance mechanisms

Author: Franck Tirode, Françoise Rédini, Dominique Heymann, Catherine Pellat-Deceunynck, Sylvanie Surget, Romain Guiho, Gaelle Picarda, Martine Berreur, Stéphane Téletchéa, Valérie Trichet, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), The work was supported by the 'Fédération Nationale Enfants et Santé,' the 'Sociétée Française de lutte contre les Cancers et les leucémies de l'Enfant et de l'Adolescent.', TIRODE, Franck, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Gene isoform, Models, Molecular, Cancer Research, Molecular Sequence Data, CASP8 and FADD-Like Apoptosis Regulating Protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Flow cytometry, Small hairpin RNA, TNF-Related Apoptosis-Inducing Ligand, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cell Line, Tumor, medicine, Humans, Protein Isoforms, Viability assay, Amino Acid Sequence, RNA, Messenger, Receptor, Molecular Biology, 030304 developmental biology, 0303 health sciences, Gene knockdown, medicine.diagnostic_test, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Molecular biology, 3. Good health, Protein Structure, Tertiary, Blot, Gene Expression Regulation, Neoplastic, Alternative Splicing, Receptors, TNF-Related Apoptosis-Inducing Ligand, Oncology, Cell culture, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Mutant Proteins, Drug Screening Assays, Antitumor
Abstract: Ewing's sarcoma (ES) is a high-grade neoplasm arising in bones of children and adolescents. Survival rate decreases from greater than 50% to only 20% after 5 years for patients not responding to treatment or presenting metastases at diagnosis. TRAIL, which has strong antitumoral activity, is a promising therapeutic candidate. To address TRAIL sensitivity, 7 human ES cell lines were used. Cell viability experiments [3′[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro-)benzene sulfonic acid hydrate (XTT) assay] showed that 4 of the 7 ES cell lines were resistant to TRAIL. Western blotting and flow cytometry analyses revealed that DR5 was uniformly expressed by all ES cell lines, whereas DR4 levels were higher in sensitive cell lines. In TRAIL-sensitive TC-71 cells, knockdown of TNFRSF10A/DR4 by short hairpin RNA (shRNA) was associated with a loss of sensitivity to TRAIL, in spite of DR5 presence. Interestingly, we identified a new transcript variant that results from an alternative splicing and encodes a 310–amino acid protein which corresponds to the 468 aa of DR4 original isoform but truncated of aa 11 to 168 within the extracellular TRAIL-binding domain. According to modeling studies, the contact of this new DR4 isoform (bDR4) with TRAIL seemed largely preserved. The overexpression of bDR4 in a TRAIL-resistant cell line restored TRAIL sensitivity. TRAIL resensitization was also observed after c-FLIP knockdown by shRNA in two TRAIL-resistant cell lines, as shown by XTT assay and caspase-3 assay. The results presented in this study showed that DR4, both as the complete form or as its new short isoform, is involved in TRAIL sensitivity in ES. Mol Cancer Res; 10(3); 336–46. ©2012 AACR.
Published: 2012
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32. Bone Sarcomas: From Biology to Targeted Therapies

Author: Birgit Geoerger, Franck Tirode, Nadège Corradini, Valérie Laurence, Perrine Marec-Berard, Natacha Enz-Werle, Sophie Piperno-Neumann, Odile Oberlin, Angela Di Giannatale, Françoise Rédini, Laurence Brugières, Jean-Claude Gentet, Nathalie Gaspar, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département d'Oncologie Pédiatrique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre Léon Bérard [Lyon], Hôpital de la Timone [CHU - APHM] (TIMONE), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and TIRODE, Franck
Subjects: Oncology, medicine.medical_specialty, Pathology, Article Subject, Metastatic phenotype, Histological response, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, Bone Sarcoma, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bone tumours, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Radiology, Nuclear Medicine and imaging, Young adult, Treatment resistance, 030304 developmental biology, 0303 health sciences, business.industry, Patient survival, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Tumour volume, business
Abstract: International audience; Primary malignant bone tumours, osteosarcomas, and Ewing sarcomas are rare diseases which occur mainly in adolescents and young adults. With the current therapies, some patients remain very difficult to treat, such as tumour with poor histological response to preoperative CT (or large initial tumour volume for Ewing sarcomas not operated), patients with multiple metastases at or those who relapsed. In order to develop new therapies against these rare tumours, we need to unveil the key driving factors and molecular abnormalities behind the malignant characteristics and to broaden our understanding of the phenomena sustaining the metastatic phenotype and treatment resistance in these tumours. In this paper, starting with the biology of these tumours, we will discuss potential therapeutic targets aimed at increasing local tumour control, limiting metastatic spread, and finally improving patient survival.
Published: 2012
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33. De novo motif identification improves the accuracy of predicting transcription factor binding sites in ChIP-Seq data analysis

Author: Emmanuel Barillot, Didier Surdez, Noëlle Guillon, Valentina Boeva, Anthony P. Fejes, Franck Tirode, Olivier Delattre, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genome Sciences Center [[Vancouver, British Columbia] Canada], Curie Institute, the « Ligue Nationale contre le Cancer »(V.B., E.B., D.S., N.G., F.T. and O.D. are members oflabeled team, the project was also supported by the CITprogram ‘Carte d’Identite´ des Tumeurs’), InstitutNational de la Sante´ et de la Recherche Me´dicale andthe Agence Nationale de la Recherche (SITCONproject)., Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and TIRODE, Franck
Subjects: Chromatin Immunoprecipitation, Oncogene Proteins, Fusion, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Consensus Sequence, Genetics, Consensus sequence, Humans, Regulatory Elements, Transcriptional, Binding site, Transcription factor, 030304 developmental biology, 0303 health sciences, Binding Sites, Base Sequence, Proto-Oncogene Protein c-fli-1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sequence Analysis, DNA, ChIP-sequencing, DNA binding site, CTCF, 030220 oncology & carcinogenesis, Methods Online, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA-Binding Protein EWS, TRANSFAC, Chromatin immunoprecipitation, Algorithms, Transcription Factors
Abstract: Dramatic progress in the development of next-generation sequencing technologies has enabled accurate genome-wide characterization of the binding sites of DNA-associated proteins. This technique, baptized as ChIP-Seq, uses a combination of chromatin immunoprecipitation and massively parallel DNA sequencing. Other published tools that predict binding sites from ChIP-Seq data use only positional information of mapped reads. In contrast, our algorithm MICSA (Motif Identification for ChIP-Seq Analysis) combines this source of positional information with information on motif occurrences to better predict binding sites of transcription factors (TFs). We proved the greater accuracy of MICSA with respect to several other tools by running them on datasets for the TFs NRSF, GABP, STAT1 and CTCF. We also applied MICSA on a dataset for the oncogenic TF EWS-FLI1. We discovered >2000 binding sites and two functionally different binding motifs. We observed that EWS-FLI1 can activate gene transcription when (i) its binding site is located in close proximity to the gene transcription start site (up to approximately 150 kb), and (ii) it contains a microsatellite sequence. Furthermore, we observed that sites without microsatellites can also induce regulation of gene expression--positively as often as negatively--and at much larger distances (up to approximately 1 Mb).
Published: 2010
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34. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity

Author: Véronique Brouste, Jean-Yves Blay, Aurélien de Reyniès, Carlo Lucchesi, Pauline Lagarde, Dominique Vince-Ranchère, Audrey Kauffmann, Agnès Leroux, F. Collin, Alain Aurias, Sébastien Salas, Franck Tirode, Philippe Terrier, Binh Bui, Jean-Michel Coindre, Louis Guillou, Sylvie Bonvalot, Frédéric Chibon, Gaëlle Pérot, Axel Le Cesne, TIRODE, Franck, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, Medical Oncology Unit, S. Camillo-Forlanini Hospital, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Département d'oncologie médicale, UNICANCER-UNICANCER, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Centre Léon Bérard [Lyon], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Oncology - Pathology - Anatomy, Institute of Pathology-University of Bern, Centre Alexis Vautrin (CAV), Service de Pathologie, This work was supported by grants from the French Institut National du Cancer, the French Projets Hospitaliers de Recherche Clinique program, the European Connective Tissue Cancer Network, the Curie Institute, the Bergonie Cancer Institute and l’INSERM. The construction of the human BAC array was supported by grants from the Carte d’Identité des Tumeurs program of the French Ligue Nationale Contre le Cancer., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, Male, medicine.medical_specialty, Pathology, Multivariate analysis, Expression Signature, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Biochemistry, Genetics and Molecular Biology, Disease-Free Survival, Metastasis, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Neoplasms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, Humans, Neoplasm Metastasis, Gene, 030304 developmental biology, Aged, 0303 health sciences, Training set, Genome complexity, business.industry, Gene Expression Profiling, Sarcoma, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Middle Aged, medicine.disease, Prognosis, 3. Good health, Gene expression profiling, Treatment Outcome, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, business, Forecasting
Abstract: Comment inGenetics: A new method for predicting metastasis in sarcomas. [Nat Rev Clin Oncol. 2010]; International audience; Sarcomas are heterogeneous and aggressive mesenchymal tumors. Histological grading has so far been the best predictor for metastasis-free survival, but it has several limitations, such as moderate reproducibility and poor prognostic value for some histological types. To improve patient grading, we performed genomic and expression profiling in a training set of 183 sarcomas and established a prognostic gene expression signature, complexity index in sarcomas (CINSARC), composed of 67 genes related to mitosis and chromosome management. In a multivariate analysis, CINSARC predicts metastasis outcome in the training set and in an independent 127 sarcomas validation set. It is superior to the Fédération Francaise des Centres de Lutte Contre le Cancer grading system in determining metastatic outcome for sarcoma patients. Furthermore, it also predicts outcome for gastrointestinal stromal tumors (GISTs), breast carcinomas and lymphomas. Application of the signature will permit more selective use of adjuvant therapies for people with sarcomas, leading to decreased iatrogenic morbidity and improved outcomes for such individuals.
Published: 2010
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35. The oncogenic EWS-FLI1 protein binds in vivo GGAA microsatellite sequences with potential transcriptional activation function

Author: Franck Tirode, Andrei Zynovyev, Valentina Boeva, Emmanuel Barillot, Olivier Delattre, Noëlle Guillon, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, the Institut Curie, the Ligue Nationale contre leCancer (Equipe labellisée and CIT program) and the Agence Nationale de la Recherche (SITCON project), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and TIRODE, Franck
Subjects: Transcriptional Activation, Proto-Oncogene Protein c-fli-1, Adolescent, Oncogene Proteins, Fusion, lcsh:Medicine, Computational Biology/Transcriptional Regulation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Transcriptional regulation, Humans, Binding site, lcsh:Science, Transcription factor, Gene, Genetics and Genomics/Cancer Genetics, 030304 developmental biology, Genetics, Regulation of gene expression, 0303 health sciences, Reporter gene, Multidisciplinary, Base Sequence, lcsh:R, fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Gene Expression Regulation, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:Q, Oncology/Pediatric Oncology, RNA-Binding Protein EWS, Research Article, Computational Biology/Genomics, Microsatellite Repeats, Transcription Factors
Abstract: International audience; The fusion between EWS and ETS family members is a key oncogenic event in Ewing tumors and important EWS-FLI1 target genes have been identified. However, until now, the search for EWS-FLI1 targets has been limited to promoter regions and no genome-wide comprehensive analysis of in vivo EWS-FLI1 binding sites has been undertaken. Using a ChIP-Seq approach to investigate EWS-FLI1-bound DNA sequences in two Ewing cell lines, we show that this chimeric transcription factor preferentially binds two types of sequences including consensus ETS motifs and microsatellite sequences. Most bound sites are found outside promoter regions. Microsatellites containing more than 9 GGAA repeats are very significantly enriched in EWS-FLI1 immunoprecipitates. Moreover, in reporter gene experiments, the transcription activation is highly dependent upon the number of repeats that are included in the construct. Importantly, in vivo EWS-FLI1-bound microsatellites are significantly associated with EWS-FLI1-driven gene activation. Put together, these results point out the likely contribution of microsatellite elements to long-distance transcription regulation and to oncogenesis.
Published: 2009
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36. Cellules souches et tumeurs conjonctives : le sarcome d’Ewing

Author: Olivier Delattre, Franck Tirode, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and TIRODE, Franck
Subjects: 0303 health sciences, Conjunctiva, Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Sarcoma ewing, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Stem cell, 030304 developmental biology
Abstract: International audience; This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright
Published: 2008
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37. EWS/FLI-1 Silencing and Gene Profiling of Ewing Cells Reveal Downstream Oncogenic Pathways and a Crucial Role for Repression of Insulin-Like Growth Factor Binding Protein 3

Author: Franck Tirode, Pinchas Cohen, Olivier Delattre, Alexandre Prieur, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and TIRODE, Franck
Subjects: Oncogene Proteins, Fusion, Molecular Sequence Data, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, RNA interference, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Gene silencing, Humans, Gene Silencing, Molecular Biology, Transcription factor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Transcriptional Regulation, 0303 health sciences, Base Sequence, Proto-Oncogene Protein c-fli-1, Gene Expression Profiling, fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Artificial Gene Fusion, Gene expression profiling, Gene Expression Regulation, Neoplastic, Insulin-Like Growth Factor Binding Protein 3, 030220 oncology & carcinogenesis, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA Interference, Signal transduction, RNA-Binding Protein EWS, Signal Transduction, Transcription Factors
Abstract: Ewing tumors are characterized by abnormal transcription factors resulting from the oncogenic fusion of EWS with members of the ETS family, most commonly FLI-1. RNA interference targeted to the junction between EWS and FLI-1 sequences was used to inactivate the EWS/FLI-1 fusion gene in Ewing cells and to explore the resulting phenotype and alteration of the gene expression profile. Loss of expression of EWS/FLI-1 resulted in the complete arrest of growth and was associated with a dramatic increase in the number of apoptotic cells. Gene profiling of Ewing cells in which the EWS/FLI-1 fusion gene had been inactivated identified downstream targets which could be grouped in two major functional clusters related to extracellular matrix structure or remodeling and regulation of signal transduction pathways. Among these targets, the insulin-like growth factor binding protein 3 gene (IGFBP-3), a major regulator of insulin-like growth factor 1 (IGF-1) proliferation and survival signaling, was strongly induced upon treating Ewing cells with EWS/FLI-1-specific small interfering RNAs. We show that EWS/FLI-1 can bind the IGFBP-3 promoter in vitro and in vivo and can repress its activity. Moreover, IGFBP-3 silencing can partially rescue the apoptotic phenotype caused by EWS/FLI-1 inactivation. Finally, IGFBP-3-induced Ewing cell apoptosis relies on both IGF-1-dependent and -independent pathways. These findings therefore identify the repression of IGFBP-3 as a key event in the development of Ewing's sarcoma.
Published: 2004
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38. Three-Hybrid Screens: Inducible Third-Party Systems

Author: Jean-Marc Egly, Björn Sandrock, Franck Tirode, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), TIRODE, Franck, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I
Subjects: 0303 health sciences, 03 medical and health sciences, Information retrieval, Text mining, business.industry, Computer science, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030302 biochemistry & molecular biology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, business, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 030304 developmental biology
Abstract: International audience; 1. INTRODUCTION Recent studies have brought up the existence of several molecular complexes either stable, like the RNA polymerase II holoenzyme, transcription factor TFIID and mediators, or transient as could be observed in the various steps of the transcription process e.g. initiation, elongation and termination. These observations point out the fact that regulation of different cellular mechanisms is orchestrated by interactions between molecular species either to modify proteins or to position one of them within a complex that then will be functional. Several techniques such as affinity precipitation, glycerol gradient sedimentation and the yeast two-hybrid system are currently used to study protein-protein interactions (1). These various methods, usually investigating the connection between two partners, keep in account only the strong (and stable) interactions and neglect the weaker ones. Considering the complexes studied so far, it is suspected and sometimes shown that interactions often occur between more than two proteins, e.g. to stabilize the complex. In an effort to understand the various biological mechanisms-and in our case gene expression regulation-, we were interested in developing the yeast three-(or tri-)hybrid system. The three-hybrid system, as illustrated in figure 1, is based on the reconstitution of a transcriptional activator complex either to search for or to study a protein that interacts with two others and to acquire information about ternary complex assembly (2). This technique detects direct or mediated interactions between two fusion proteins that contain either a DNA binding domain (DBD; the DBD-X protein) or an activation domain (AD; the AD-Y protein). In some cases, when these two hybrid proteins interact weakly or not at all, a third partner (the protein Z) is necessary to promote (to induce) the formation of the transcriptional activator allowing the transcription of the reporter genes. Thus, specific and stable protein-protein interactions between X, Y and Z lead to the activation of the reporter genes that are integrated in the yeast genome. The HIS3 reporter gene contains a specific DNA sequence which can be recognized by the DBD of the transcriptional activator. Activation of the HIS3 gene permits the endogenous synthesis of histidine allowing the yeast to grow on histidine-lacking media. Activation of the LacZ gene, another reporter gene containing the same DNA binding element, will lead to the synthesis of the β-galactosidase (β-Gal) that catalyses the transformation of either X-Gal (5-bromo-4-chloro-3-indolyl β-D-galactopyranoside) or ONPG (o-nitrophenyl-β-D-galactopyranoside) into a detectable blue or yellow product, respectively. There are several options to reconstitute the transcriptional activator: (i) the third partner Z can act as a bridging factor (Fig.1A) by interacting with both the DBD-X and AD-Y, thus allowing the DNA-binding protein X to target the basal transcription machinery; (ii) In case of weak interactions, Z may function as a stabilising factor (Fig.1B) that strengthens the interaction between X and Y; (iii) In some other cases, reconstitution of the transcriptional activator requires some post-transcriptional modifications of one of the two partners, in order to allow interaction between X and Y. The third partner Z will then be a regulating factor (Fig.1C), an enzyme that will not necessarily be part of the reconstituted transcriptional activator. When DBD-X and AD-Y are sufficient to reconstitute a stable transcriptional activator, the three-hybrid system can also be used for the search of inhibitors. In this case, the Z partner can act as an inhibitor (Fig.1D) by interacting with, or enzymatically modifying, one of the two main partners, thus preventing their interactions. This will result in the inhibition of the expression of the reporter genes followed by growth restriction on histidine-lacking media as well as repression of the β-Gal activity.
Published: 2001
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39. A Conditionally Expressed Third Partner Stabilizes or Prevents the Formation of a Transcriptional Activator in a Three-hybrid System

Author: Claudia Malaguti, Jacques Camonis, Franck Tirode, Francisco Romero, Jean-Marc Egly, Ricardo Attar, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Institut Cochin de Génétique Moléculaire, Bristol Meyer Squibb [Princeton, NJ, USA], Génétique et expression des oncogènes, Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the INSERM, the CNRS, and the Ministère de la Recherche et de l’Enseignement Supérieur., Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and TIRODE, Franck
Subjects: Cyclin H, Recombinant Fusion Proteins, Genetic Vectors, Molecular Sequence Data, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, Transcription Factors, TFII, 03 medical and health sciences, Transformation, Genetic, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cyclin-dependent kinase, Transcription (biology), Cyclins, Gene Expression Regulation, Fungal, Proto-Oncogene Proteins, Yeasts, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cloning, Molecular, Molecular Biology, Transcription factor, 030304 developmental biology, 0303 health sciences, Base Sequence, biology, Activator (genetics), [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Fusion protein, Molecular biology, Cyclin-Dependent Kinases, Neoplasm Proteins, Cell biology, Proto-Oncogene Proteins c-raf, Transcription Factor TFIIH, ras Proteins, biology.protein, Transcription factor II H, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Artifacts, Cyclin-Dependent Kinase-Activating Kinase, 030217 neurology & neurosurgery, Protein Binding, Transcription Factors
Abstract: International audience; We describe a three-hybrid system that involves three polypeptides that allow or prevent the formation of the transcriptional activator. Beside the two-hybrid fusion proteins, the third partner is under the control of the Met25 promoter, which is positively regulated in medium lacking methionine. We document a situation where such a third partner promotes interaction between two proteins, one fused to a DNA-binding domain and the other fused to an activator domain. This is demonstrated for cdk7-MAT1 interaction stabilized by the presence of cyclin H; these three polypeptides are found either free or associated with the transcription/DNA repair factor TFIIH. We also document the capacity of our system to conditionally inhibit the interaction between two polypeptides that otherwise elicit a positive two-hybrid response. This is demonstrated for Ras-Raf interaction precluded by an excess of Raf. The presence of a methionine-regulated promoter provides an "on" or "off" switch for the formation of the transcriptional activator, thus also providing an excellent control to evaluate the activation or inhibition properties of the third partner.
Published: 1997
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40. Mesenchymal Stem Cell Features of Ewing Tumors

Author: Bruno Delorme, Pierre Charbord, Karine Laud-Duval, Olivier Delattre, Alexandre Prieur, Franck Tirode, TIRODE, Franck, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), ESPRI-EA3855, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cancer Research, Proto-Oncogene Protein c-fli-1, Cellular differentiation, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Gene silencing, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Progenitor, DNA Primers, 0303 health sciences, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Mesenchymal stem cell, fungi, Cell Differentiation, Mesenchymal Stem Cells, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Phenotype, STEMCELL, Cell biology, Oncology, Cell culture, 030220 oncology & carcinogenesis, Immunology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract: SummaryThe cellular origin of Ewing tumor (ET), a tumor of bone or soft tissues characterized by specific fusions between EWS and ETS genes, is highly debated. Through gene expression analysis comparing ETs with a variety of normal tissues, we show that the profiles of different EWS-FLI1-silenced Ewing cell lines converge toward that of mesenchymal stem cells (MSC). Moreover, upon EWS-FLI1 silencing, two different Ewing cell lines can differentiate along the adipogenic lineage when incubated in appropriate differentiation cocktails. In addition, Ewing cells can also differentiate along the osteogenic lineage upon long-term inhibition of EWS-FLI1. These in silico and experimental data strongly suggest that the inhibition of EWS-FLI1 may allow Ewing cells to recover the phenotype of their MSC progenitor.
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