Descriptor: "MESH: DNA, Neoplasm" - Searchworks@Jio Institute Digital Library Search Results

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40 results on '"MESH: DNA, Neoplasm"'

1. Regulation of ALT-associated homology-directed repair by polyADP-ribosylation

Author: Ian D. Waddell, Robert W. Sobol, Kate M. Smith, Justin L. Roncaioli, Felipe da Veiga Leprevost, Song My Hoang, Dattatreya Mellacharevu, Dominique Ray-Gallet, Michelle L. Lynskey, Roderick J. O’Sullivan, Ragini Bhargava, Jonathan Barroso-González, Nicole Kaminski, Geneviève Almouzni, Anne R. Wondisford, Jianfeng Li, Donald J. Ogilvie, Alexey I. Nesvizhskii, Dominic I. James, Callen T. Wallace, Simon C. Watkins, Laura García-Expósito, University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Manchester [Manchester], University of Michigan [Ann Arbor], University of Michigan System, University of South Alabama, Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and HAL-SU, Gestionnaire
Subjects: MESH: Signal Transduction, Poly Adenosine Diphosphate Ribose, Cell Cycle Proteins, Histones, Poly ADP Ribosylation, 0302 clinical medicine, Structural Biology, MESH: RNA, Small Interfering, RNA, Small Interfering, MESH: Histones, 0303 health sciences, PARG, MESH: X-linked Nuclear Protein, biology, MESH: Histone Chaperones, DNA, Neoplasm, MESH: Transcription Factors, MESH: Gene Expression Regulation, Neoplastic, Telomere, Chromatin, Cell biology, Gene Expression Regulation, Neoplastic, MESH: Recombinational DNA Repair, Histone, MESH: Poly Adenosine Diphosphate Ribose, MESH: Epithelial Cells, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Poly(ADP-ribose) Polymerases, Signal Transduction, G2 Phase, X-linked Nuclear Protein, MESH: Cell Line, Tumor, Glycoside Hydrolases, DNA repair, DNA damage, MESH: DNA, Neoplasm, Article, MESH: Chromatin, MESH: Telomere Homeostasis, Homology directed repair, 03 medical and health sciences, MESH: Cell Cycle Proteins, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Glycoside Hydrolases, Humans, Histone Chaperones, Molecular Biology, ATRX, 030304 developmental biology, MESH: DNA Damage, MESH: Humans, MESH: Poly ADP Ribosylation, MESH: Poly(ADP-ribose) Polymerases, Recombinational DNA Repair, Telomere Homeostasis, Epithelial Cells, MESH: G2 Phase, MESH: Protein Processing, Post-Translational, MESH: HeLa Cells, biology.protein, MESH: Telomere, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, DNA Damage, HeLa Cells, Transcription Factors
Abstract: International audience; The synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and recruits DNA-repair complexes to damaged chromatin. PAR degradation by poly(ADP-ribose) glycohydrolase (PARG) is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative lengthening of telomeres (ALT). Proteomic analyses uncover a new role for poly(ADP-ribosyl)ation (PARylation) in regulating the chromatin-assembly factor HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during the G2 phase and is required for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells that is mitigated by re-expression of ATRX, a protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response to ATRX deficiency that pervades ALT cancers.
Published: 2020
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2. Erroneous identification of APOBEC3-edited chromosomal DNA in cancer genomics

Author: Caval, Mohamed S. Bouzidi, Jean-Pierre Vartanian, Michel Henry, Rodolphe Suspène, Simon Wain-Hobson, Rétrovirologie Moléculaire, Institut Pasteur [Paris] (IP), and This work was supported by grants from the Institut Pasteur, INCa and the CNRS. VC and MSB were supported by OSEO and the Ligue Nationale Contre le Cancer.
Subjects: MESH: Neoplasm Proteins, CD4-Positive T-Lymphocytes, Cancer Research, [SDV]Life Sciences [q-bio], MESH: beta Catenin, Cytidine, medicine.disease_cause, Nucleic Acid Denaturation, Genome, Polymerase Chain Reaction, law.invention, Cytosine Deaminase, chemistry.chemical_compound, MESH: Liver Neoplasms, law, APOBEC Deaminases, APOBEC3A, MESH: Carcinoma, Hepatocellular, Polymerase chain reaction, Cells, Cultured, beta Catenin, Genetics, Recombination, Genetic, Mutation, Liver Neoplasms, MESH: APOBEC Deaminases, Temperature, MESH: CD4-Positive T-Lymphocytes, APOBEC3, DNA, Neoplasm, MESH: Temperature, MESH: Hepatitis C, Chronic, Nuclear DNA, Neoplasm Proteins, Oncology, MESH: Recombination, Genetic, MESH: Interferon-alpha, MESH: Cytidine, MESH: Cells, Cultured, MESH: Mutation, Carcinoma, Hepatocellular, MESH: Hepatitis B, Chronic, MESH: DNA, Neoplasm, Context (language use), Genomics, MESH: Nucleic Acid Denaturation, Biology, MESH: Phytohemagglutinins, Hepatitis B, Chronic, Cytidine Deaminase, medicine, Humans, 3DPCR, Phytohemagglutinins, MESH: Cytidine Deaminase, cancer genomics, MESH: Humans, MESH: Cytosine Deaminase, hypermutation, Interferon-alpha, MESH: Interleukin-2, MESH: Polymerase Chain Reaction, Genetics and Genomics, Hepatitis C, Chronic, chemistry, Interleukin-2, DNA
Abstract: International audience; Background: The revolution in cancer genomics shows that the dominant mutations are CG->TA transitions. The sources of these mutations are probably two host cell cytidine deaminases APOBEC3A and APOBEC3B. The former in particular can access nuclear DNA and monotonously introduce phenomenal numbers of C->T mutations in the signature 5'TpC context. These can be copied as G->A transitions in the 5'GpA context.Methods: DNA hypermutated by an APOBEC3 enzyme can be recovered by a technique called 3DPCR, which stands for differential DNA denaturation PCR. This method exploits the fact that APOBEC3-edited DNA is richer in A+T compared with the reference. We explore explicitly 3DPCR error using cloned DNA.Results: Here we show that the technique has a higher error rate compared with standard PCR and can generate DNA strands containing both C->T and G->A mutations in a 5'GpCpR context. Sequences with similar traits have been recovered from human tumour DNA using 3DPCR.Conclusions: Differential DNA denaturation PCR cannot be used to identify fixed C->T transitions in cancer genomes. Presently, the overall mutation frequency is ∼10(4)-10(5) base substitutions per cancer genome, or 0.003-0.03 kb(-1). By contrast, the 3DPCR error rate is of the order of 4-20 kb(-1) owing to constant selection for AT DNA and PCR-mediated recombination. Accordingly, sequences recovered by 3DPCR harbouring mixed C->T and G->A mutations associated with the 5'GpC represent artefacts.
Published: 2014
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3. Oncogene abnormalities in a series of primary melanomas of the sinonasal tract: NRAS mutations and cyclin D1 amplification are more frequent than KIT or BRAF mutations

Author: Nicolas Ortonne, Issam Abd Alsamad, Nicolas Dumaz, Meriem Chraybi, Maryse Baia, Christiane Copie-Bergman, Jocelyne André, Service d'anatomie et cytologie pathologiques, CHI Créteil, INSERM U955, équipe 9, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, and Guellaen, Georges
Subjects: Male, Neuroblastoma RAS viral oncogene homolog, MESH: Cyclin D1, DNA Mutational Analysis, cyclin D1, sinonasal melanoma, medicine.disease_cause, MESH: Gene Amplification, GTP Phosphohydrolases, MESH: Aged, 80 and over, 0302 clinical medicine, Epidermal growth factor receptor, MESH: DNA Mutational Analysis, Melanoma, Aged, 80 and over, MESH: Aged, 0303 health sciences, Mutation, MESH: Middle Aged, medicine.diagnostic_test, biology, KIT, DNA, Neoplasm, Middle Aged, CCND1 amplification, 3. Good health, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Female, MESH: Membrane Proteins, Paranasal Sinus Neoplasms, Proto-Oncogene Proteins B-raf, MESH: Mutation, MESH: GTP Phosphohydrolases, MESH: Melanoma, MESH: DNA, Neoplasm, NRAS, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Cyclin D1, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, neoplasms, Aged, Retrospective Studies, 030304 developmental biology, MESH: Paranasal Sinus Neoplasms, MESH: Proto-Oncogene Proteins B-raf, MESH: Humans, Gene Amplification, Membrane Proteins, MESH: Retrospective Studies, Sinonasal Tract, medicine.disease, MESH: Male, BRAF mutation, Primary malignant melanoma of sinonasal tract, Cancer research, biology.protein, MESH: Female, Fluorescence in situ hybridization
Abstract: International audience; Primary malignant melanoma of sinonasal tract is a rare but severe form of melanoma. We retrospectively analyzed 17 cases and focused on the histologic presentation and the expression of c-Kit, epidermal growth factor receptor (EGFR), cyclin D1/Bcl-1, PS100, and HMB45 and searched for BRAF, NRAS, and KIT mutations that are known to be associated with melanoma subtypes, together with amplifications of KIT, cyclin D1, cyclin-dependent kinase 4, MDM2, and microphthalmia-associated transcription factor using quantitative polymerase chain reaction. In most cases (78%), an in situ component was evidenced. Invasive components were composed of diffuse areas of rhabdoid, epithelioid, or spindle cells and, in most cases, lacked inflammatory reaction, suggesting that an immune escape phenomenon probably develops when the disease progresses. EGFR was rarely and weakly expressed in the in situ component of 2 cases. None of the investigated case showed BRAF V600E, but 1 had a D594G mutation. NRAS mutations in exon 2 (G12D or G12A) were found in 3 cases (18%), and a KIT mutation in exon 11 (L576P), in 1, whereas c-Kit was expressed at the protein level in half of the cases. Amplifications of cyclin D1 were evidenced in 5 cases, confirmed in 3 by fluorescence in situ hybridization, but this was not always correlated with protein expression, found in 8 patients (62.5%), 3 having no significant amplification. In conclusion, primary malignant melanoma of sinonasal tract is not associated with BRAF V600E mutations. Instead, NRAS or KIT mutations and cyclin D1 amplification can be found in a proportion of cases, suggesting that primary malignant melanoma of sinonasal tract is heterogeneous at the molecular level and should not be sensitive to therapeutic approaches aiming at BRAF.
Published: 2013
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4. Plasma Circulating Tumor DNA Levels for the Monitoring of Melanoma Patients: Landscape of Available Technologies and Clinical Applications

Author: Jean-Luc Coll, Joel Plumas, Benoit Busser, Amandine Hurbin, Julie Charles, Laurence Chaperot, Patrice Faure, Marie Therese Leccia, Julien Lupo, Stéphane Mouret, Pierre Hainaut, Lucie Sancey, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Biochemistry Pharmacology and Toxicology Department, Centre Hospitalo-Universitaire de Grenoble, Laboratoire de Virologie [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département de dermatologie, allergologie et photobiologie [Hôpital Michallon du CHU Grenoble Alpes], Centre Hospitalier Universitaire [Grenoble] (CHU)-Hôpital Michallon, Hypoxie et physiopathologies cardiovasculaire et respiratoire, Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Thomas, Frank
Subjects: 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, MESH: Neoplasm Proteins, Article Subject, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Melanoma, medicine.medical_treatment, lcsh:Medicine, MESH: DNA, Neoplasm, MESH: Monitoring, Physiologic, Review Article, Bioinformatics, Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Circulating tumor cell, Humans, Medicine, Digital polymerase chain reaction, Neoplasm Metastasis, Melanoma, Monitoring, Physiologic, MESH: Humans, General Immunology and Microbiology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], business.industry, lcsh:R, High mortality, MESH: Polymerase Chain Reaction, DNA, Neoplasm, General Medicine, medicine.disease, MESH: Neoplasm Metastasis, Neoplasm Proteins, 3. Good health, Biomarker, 030104 developmental biology, Circulating tumor DNA, 030220 oncology & carcinogenesis, Cancer research, business
Abstract: Melanoma is a cutaneous cancer with an increasing worldwide prevalence and high mortality due to unresectable or metastatic stages. Mutations inBRAF,NRAS, orKITare present in more than 60% of melanoma cases, but a useful blood-based biomarker for the clinical monitoring of melanoma patients is still lacking. Thus, the analysis of circulating tumor cells (CTCs) and/or cell-free circulating tumor DNA (ctDNA) analysis from blood (liquid biopsies) appears to be a promising noninvasive, repeatable, and systemic sampling tool for detecting and monitoring melanoma. Here, we review the molecular biology-based strategies used for ctDNA quantification in melanoma patients, as well as their main clinical applications. Droplet digital PCR (ddPCR) and next generation sequencing (NGS) technologies appear to be two versatile and complementary strategies to study rare variant mutations for the detection and monitoring of melanoma progression. Among the different clinical uses of ctDNA, we highlight the assessment of molecular heterogeneity and the identification of genetic determinants for targeted therapy as well as the analysis of acquired resistance. Importantly, ctDNA quantification might also be a novel biomarker with a prognostic value for melanoma patients.
Published: 2017
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5. A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker

Author: Géraldine Perkins, Anais Pujals, Cecile Charpy, Pascaline Aucouturier, Aziz Zaanan, Valérie Taly, Darren R. Link, Corinne Normand, Jean-François Emile, Sanam Peyvandi, Sonia Garrigou, Iradj Sobhani, Karla Perez-Toralla, Denis Pezet, Delphine Le Corre, Philippe Nizard, Ralph Niarra, Frédéric Bibeau, Eleonora Zonta, Fanny Garlan, Claire Mulot, Pierre Laurent-Puig, J. Brian Hutchison, Olivier Bouché, Gilles Chatellier, Caroline Barau, Audrey Didelot, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Early detection of Colon Cancer using Molecular Markers and Microbiota (EA 7375) (EC2M3), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Universitaires des Saints-Pères, Centre d'Investigation Clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Centre Hospitalier Universitaire de Reims (CHU Reims), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], CHU Clermont-Ferrand, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), RainDance Technologies, Inc., Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Herrada, Anthony
Subjects: Male, 0301 basic medicine, Pathology, Colorectal cancer, Clinical Biochemistry, Tumor M2-PK, Polymerase Chain Reaction, law.invention, 0302 clinical medicine, MESH: DNA Methylation, law, Neuropeptide Y, Digital polymerase chain reaction, Polymerase chain reaction, MESH: Aged, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Wnt signaling pathway, DNA, Neoplasm, 3. Good health, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, DNA methylation, Biomarker (medicine), Female, MESH: Biomarkers, Tumor, Colorectal Neoplasms, medicine.medical_specialty, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, medicine, Humans, MESH: Neuropeptide Y, Adaptor Proteins, Signal Transducing, Aged, MESH: Adaptor Proteins, Signal Transducing, MESH: Humans, Biochemistry (medical), Cancer, MESH: Polymerase Chain Reaction, DNA Methylation, medicine.disease, MESH: Male, Repressor Proteins, 030104 developmental biology, Cancer research, MESH: Female, MESH: Colorectal Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BACKGROUNDCirculating tumor DNA (ctDNA) has emerged as a good candidate for tracking tumor dynamics in different cancer types, potentially avoiding repeated tumor biopsies. Many different genes can be mutated within a tumor, complicating procedures for tumor monitoring, even with highly sensitive next-generation sequencing (NGS) strategies. Droplet-based digital PCR (dPCR) is a highly sensitive and quantitative procedure, allowing detection of very low amounts of circulating tumor genetic material, but can be limited in the total number of target loci monitored.METHODSWe analyzed hypermethylation of 3 genes, by use of droplet-based dPCR in different stages of colorectal cancer (CRC), to identify universal markers for tumor follow-up.RESULTSHypermethylation of WIF1 (WNT inhibitory factor 1) and NPY (neuropeptide Y) genes was significantly higher in tumor tissue compared to normal tissue, independently of tumor stage. All tumor tissues appeared positive for one of the 2 markers. Methylated ctDNA (MetctDNA) was detected in 80% of metastatic CRC and 45% of localized CRC. For samples with detectable mutations in ctDNA, MetctDNA and mutant ctDNA (MutctDNA) fractions were correlated. During follow-up of different stage CRC patients, MetctDNA changes allowed monitoring of tumor evolution.CONCLUSIONSThese results indicate that MetctDNA could be used as a universal surrogate marker for tumor follow-up in CRC patients, and monitoring MetctDNA by droplet-based dPCR could avoid the need for monitoring mutations.
Published: 2016
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6. Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake

Author: Fabien Zoulim, Marie-Pierre Lambert, Massimo Tommasino, Zdenko Herceg, Jörg Tost, Jean-Yves Scoazec, Anupam Paliwal, Pierre Hainaut, Thomas Vaissière, Bakary S. Sylla, Isabelle Chemin, 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), Interactions Bactéries-Cellules (UIBC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), International Agency for Cancer Research (IACR), Equipe 16, 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]-Université Claude Bernard Lyon 1 (UCBL), Service d'hépatologie et de gastroentérologie, Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon (CRCL), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Sect Mech Carcinogenesis, equipe 4, Laboratoire Central d'Anatomie et de Cytologie Pathologiques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Recherche en Cancérologie de Lyon (CRCL), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), 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 ), Interactions Bactéries-Cellules ( UIBC ), Institut National de la Recherche Agronomique ( INRA ) -Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), International Agency for Cancer Research ( IACR ), International Agency for Cancer Research, 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 ) -Université Claude Bernard Lyon 1 ( UCBL ), Hospices Civils de Lyon ( HCL ) -Hôtel-Dieu-Hospices Civils de Lyon ( HCL ) -Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer ( CIRC - IARC ), Organisation mondiale de la santé (OMS/WHO), international Agency for Research on Cancer - IARC, Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), 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 National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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]-Université Claude Bernard Lyon 1 (UCBL), Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), and Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, MESH : Liver Neoplasms, MESH : Aged, Receptors, Nicotinic, MESH: Base Sequence, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: DNA Methylation, 0302 clinical medicine, Risk Factors, MESH: Liver Neoplasms, MESH: Risk Factors, MESH : Female, MESH: Gene Silencing, MESH: Carcinoma, Hepatocellular, MESH: Glutathione S-Transferase pi, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH : Tumor Suppressor Proteins, Liver Neoplasms, RNA-Binding Proteins, DNA, Neoplasm, Hepatitis C, Methylation, Middle Aged, MESH : Adult, Hepatitis B, MESH : Risk Factors, 3. Good health, DNA-Binding Proteins, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, DNA methylation, MESH: Receptors, Nicotinic, Female, MESH : DNA Primers, MESH : DNA, Neoplasm, MESH : DNA-Binding Proteins, Adult, MESH : Carcinoma, Hepatocellular, MESH: DNA Primers, Carcinoma, Hepatocellular, Alcohol Drinking, MESH : Male, Hepatitis C virus, MESH : RNA-Binding Proteins, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Phosphoproteins, 03 medical and health sciences, MESH : Gene Silencing, medicine, Humans, MESH : Middle Aged, MESH: Tumor Suppressor Proteins, Gene Silencing, neoplasms, Aged, DNA Primers, 030304 developmental biology, MESH: Hepatitis C, Hepatitis B virus, MESH: Humans, Base Sequence, MESH : Receptors, Nicotinic, MESH: Hepatitis B, Hepatology, Tumor Suppressor Proteins, MESH : Humans, MESH : Hepatitis B, Cancer, MESH: Adult, DNA Methylation, MESH : Hepatitis C, Phosphoproteins, medicine.disease, MESH: Male, digestive system diseases, MESH : Alcohol Drinking, MESH: RNA-Binding Proteins, Glutathione S-Transferase pi, MESH : Glutathione S-Transferase pi, Immunology, MESH : Base Sequence, MESH : Phosphoproteins, MESH : DNA Methylation, MESH: Female, MESH: Alcohol Drinking, MESH: DNA-Binding Proteins
Abstract: International audience; BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the most frequent human cancers and a major cause of cancer-related death worldwide. The major risk factors for developing HCC are infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), chronic alcoholism, and aflatoxins; however, critical gene targets remain largely unknown. Herein, we sought to establish DNA methylation patterns in HCC and corresponding cirrhotic tissues and to identify DNA methylation changes associated with major risk factors. METHODS: We have established assays for quantitative analysis of DNA methylation levels in a panel of seven cancer-associated genes and repetitive elements, and combined these assays with a series of HCC tumors, associated with major risk factors, collected from two different geographical areas. RESULTS: We found a high frequency of aberrant hypermethylation of specific genes (RASSF1A, GSTP1, CHRNA3, and DOK1) in HCC tumors as compared to control cirrhotic or normal liver tissues, suggesting that aberrant hypermethylation exhibits non-random and tumor-specific patterns in HCC. Importantly, our analysis revealed an association between alcohol intake and the hypomethylation of MGMT and between hypermethylation of GSTP1 and HBV infection, indicating that hypermethylation of the genes analyzed in HCC tumors exhibits remarkably distinct patterns depending on associated risk factors. CONCLUSIONS: This study identifies aberrant DNA methylation of specific cellular genes in HCC and the major risk factors associated with these changes, providing information that could be exploited for biomarker discovery in clinics and molecular epidemiology.
Published: 2011
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7. A quality control program for mutation detection in KIT and PDGFRA in gastrointestinal stromal tumours

Author: Fabienne Escande, Jean Michel Coindre, Silvana Pilotti, Sébastien Forget, Paolo Dei Tos, Pierre Paul Bringuier, Maria Debiec-Rychter, Elena Tamborini, David Gonzalez, Nicolas Faur, L Morzuch, Isabelle Hostein, Louisa Toffolati, Sylvianne Olschwang, Jean-François Emile, Département de pathologie, Institut Bergonié - CRLCC Bordeaux, university of leuven, Department of Human Genetics, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-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 ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), 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 ), CA foncello Hospital, Department of pathology, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Laboratoire de Physique des Lasers ( LPL ), Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut Galilée-Centre National de la Recherche Scientifique ( CNRS ), biology and pathological laboratory, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Service de Pathologie, Institut Bergonié, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, UNICANCER, Radboud University Medical Center [Nijmegen], Centre de Recherche en Cancérologie de Marseille (CRCM / U891 Inserm), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Laboratoire de Physique des Lasers (LPL), Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), Medical University of Gdańsk, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay
Subjects: Oncology, Receptor, Platelet-Derived Growth Factor alpha, MESH : Polymorphism, Genetic, MESH: Receptor, Platelet-Derived Growth Factor alpha, DNA Mutational Analysis, MESH: Quality Control, MESH : Genotype, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, MESH : Exons, 0302 clinical medicine, Surgical oncology, Genotype, MESH: DNA Mutational Analysis, 0303 health sciences, Mutation, MESH : Gastrointestinal Stromal Tumors, GiST, Gastroenterology, MESH : Quality Control, DNA, Neoplasm, Exons, 3. Good health, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, 030220 oncology & carcinogenesis, MESH: Laboratories, MESH : DNA, Neoplasm, MESH : Mutation, MESH: Gastrointestinal Stromal Tumors, Quality Control, medicine.medical_specialty, MESH: Mutation, Gastrointestinal Stromal Tumors, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, PDGFRA, Biology, MESH : Laboratories, MESH : Proto-Oncogene Proteins c-kit, 03 medical and health sciences, Internal medicine, MESH: Polymorphism, Genetic, medicine, Humans, Genotyping, 030304 developmental biology, MESH: Humans, Polymorphism, Genetic, MESH : Humans, Hepatology, digestive system diseases, Immunology, MESH : Receptor, Platelet-Derived Growth Factor alpha, MESH: Exons, Laboratories
Abstract: International audience; BACKGROUND: Although most gastrointestinal stromal tumours (GIST) carry oncogenic mutations in KIT exons 9, 11, 13 and 17, or in platelet-derived growth factor receptor alpha (PDGFRA) exons 12, 14 and 18, around 10% of GIST are free of these mutations. Genotyping and accurate detection of KIT/PDGFRA mutations in GIST are becoming increasingly useful for clinicians in the management of the disease. METHOD: To evaluate and improve laboratory practice in GIST mutation detection, we developed a mutational screening quality control program. Eleven laboratories were enrolled in this program and 50 DNA samples were analysed, each of them by four different laboratories, giving 200 mutational reports. RESULTS: In total, eight mutations were not detected by at least one laboratory. One false positive result was reported in one sample. Thus, the mean global rate of error with clinical implication based on 200 reports was 4.5%. Concerning specific polymorphisms detection, the rate varied from 0 to 100%, depending on the laboratory. The way mutations were reported was very heterogeneous, and some errors were detected. CONCLUSION: This study demonstrated that such a program was necessary for laboratories to improve the quality of the analysis, because an error rate of 4.5% may have clinical consequences for the patient.
Published: 2011
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8. Integrative genome-wide analysis reveals a robust genomic glioblastoma signature associated with copy number driving changes in gene expression

Author: André Le Treut, Stephan Saikali, Véronique Quillien, Marc Aubry, Marie-Dominique Galibert, Amandine Etcheverry, Abderrahmane Hamlat, Marie de Tayrac, Jean Mosser, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie [Rennes], CHU Pontchaillou [Rennes]-Hôpital Pontchaillou-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Plate-forme transcriptome, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Centre de ressources biologiques de Rennes, Service de neurochirurgie [Rennes] = Neurosurgery [Rennes], Service de Biologie, CRLCC Eugène Marquis (CRLCC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR), and De Villemeur, Hervé
Subjects: Cancer Research, Gene Dosage, MESH: Genes, erbB-1, Genome, MESH: Cadherins, MESH: Gene Dosage, 0302 clinical medicine, Gene expression, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Genetics, 0303 health sciences, MESH: Glioblastoma, GTPase-Activating Proteins, Chromosome Mapping, DNA, Neoplasm, MESH: Gene Expression Regulation, Neoplastic, Cadherins, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Metabolic Networks and Pathways, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Gene dosage, MESH: Gene Expression Profiling, 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, MESH: Chromosome Aberrations, MESH: Tumor Suppressor Proteins, Gene, MESH: Genome, Human, 030304 developmental biology, Chromosome Aberrations, MESH: Humans, Genome, Human, Microarray analysis techniques, Gene Expression Profiling, Tumor Suppressor Proteins, Genes, erbB-1, Protocadherins, Gene expression profiling, MESH: Metabolic Networks and Pathways, MESH: Oligonucleotide Array Sequence Analysis, Human genome, Glioblastoma, MESH: Chromosome Mapping
Abstract: International audience; Glioblastoma multiforme shows multiple chromosomal aberrations, the impact of which on gene expression remains unclear. To investigate this relationship and to identify putative initiating genomic events, we integrated a paired copy number and gene expression survey in glioblastoma using whole human genome arrays. Loci of recurrent copy number alterations were combined with gene expression profiles obtained on the same tumor samples. We identified a set of 406 "cis-acting DNA targeted genes" corresponding to genomic aberrations with direct copy-number-driving changes in gene expression, defined as genes with either significantly concordant or correlated changes in DNA copy number and expression. Functional annotation revealed that these genes participate in key processes of cancer cell biology, providing insights into the genetic mechanisms driving glioblastoma. The robustness of the gene selection was validated on an external microarray data set including 81 glioblastomas and 23 non-neoplastic brain samples. The integration of array CGH and gene expression data highlights a robust cis-acting DNA targeted genes signature that may be critical for glioblastoma progression, with two tumor suppressor genes PCDH9 and STARD13 that could be involved in tumor invasiveness and resistance to etoposide.
Published: 2009
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9. A Targeted Q-PCR-Based Method for Point Mutation Testing by Analyzing Circulating DNA for Cancer Management Care

Author: Alain R. Thierry, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Disease Management, medicine.disease_cause, Bioinformatics, BRAF, Plasma, Cell-free DNA, 03 medical and health sciences, Sensitivity, 0302 clinical medicine, DNA Mutational Analysis, KRAS, medicine, Circulating DNA, MESH: Neoplasms, Diagnostic, MESH: DNA Mutational Analysis, ComputingMilieux_MISCELLANEOUS, Cancer, MESH: Point Mutation, Mutation, MESH: Humans, Q-PCR, MESH: Real-Time Polymerase Chain Reaction, business.industry, Point mutation, medicine.disease, 3. Good health, 030104 developmental biology, Real-time polymerase chain reaction, Cell-free fetal DNA, 030220 oncology & carcinogenesis, Cancer research, MESH: Biomarkers, Tumor, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Blood sampling
Abstract: Circulating cell-free DNA (cfDNA) is a valuable source of tumor material available with a simple blood sampling enabling a noninvasive quantitative and qualitative analysis of the tumor genome. cfDNA is released by tumor cells and exhibits the genetic and epigenetic alterations of the tumor of origin. Circulating cell-free DNA (cfDNA) analysis constitutes a hopeful approach to provide a noninvasive tumor molecular test for cancer patients. Based upon basic research on the origin and structure of cfDNA, new information on circulating cell-free DNA (cfDNA) structure, and specific determination of cfDNA fragmentation and size, we revisited Q-PCR-based method and recently developed a the allele-specific-Q-PCR-based method with blocker (termed as Intplex) which is the first multiplexed test for cfDNA. This technique, named Intplex(®) and based on a refined Q-PCR method, derived from critical observations made on the specific structure and size of cfDNA. It enables the simultaneous determination of five parameters: the cfDNA total concentration, the presence of a previously known point mutation, the mutant (tumor) cfDNA concentration (ctDNA), the proportion of mutant cfDNA, and the cfDNA fragmentation index. Intplex(®) has enabled the first clinical validation of ctDNA analysis in oncology by detecting KRAS and BRAF point mutations in mCRC patients and has demonstrated that a blood test could replace tumor section analysis for the detection of KRAS and BRAF mutations. The Intplex(®) test can be adapted to all mutations, genes, or cancers and enables rapid, highly sensitive, cost-effective, and repetitive analysis. As regards to the determination of mutations on cfDNA Intplex(®) is limited to the mutational status of known hotspot mutation; it is a "targeted approach." However, it offers the opportunity in detecting quantitatively and dynamically mutation and could constitute a noninvasive attractive tool potentially allowing diagnosis, prognosis, theranostics, therapeutic monitoring, and follow-up of cancer patients expanding the scope of personalized cancer medicine.
Published: 2016
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10. Fourth Updated ESACP Consensus Report on Diagnostic DNA Image Cytometry

Author: Albrecht Reith, Alfred Böcking, Gunter Haroske, Håvard E. Danielsen, Françoise Giroud, P. Spieler, Martin Oberholzer, A. Gschwendtner, Jan P. A. Baak, RFMQ, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Usson, Yves
Subjects: medicine.medical_specialty, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, MEDLINE, MESH: DNA, Neoplasm, MESH: Algorithms, computer.software_genre, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, International congress, medicine, Humans, Medical physics, MESH: Neoplasms, lcsh:QH573-671, DNA Image Cytometry, Image Cytometry, 030304 developmental biology, 0303 health sciences, MESH: Humans, Task force, business.industry, lcsh:Cytology, MESH: DNA, DNA, DNA, Neoplasm, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, 030220 oncology & carcinogenesis, Other, Data mining, business, computer, Algorithms, MESH: Image Cytometry
Abstract: A task force of experts in the field of diagnostic DNA image cytometry, invited by the ESACP, and further scientists or physicians revealing experience in that diagnostic procedure (names are given in Addendum A), agreed upon the following 4th updated Consensus Report on Standardised Diagnostic DNA Image Cytometry during the 7th International Congress of that society in Caen, 2001. This report is based on the three preceding ones [6,14,17]. It deals with the following items: – Critical review and update of the definitions given in the 1997 Consensus Update; – Review and detailed description of basic terms, principles and algorithms for diagnostic interpretation; – Recommendations concerning diagnostic or prognostic applications in specific fields of tumour pathology. This update is not aimed to substitute the 1997 consensus, but to make necessary addenda and give more detailed descriptions of those items not unequivocally to interpret by potential users of the methodology.
Published: 2001

11. Validation of a yeast functional assay for p53 mutations using clonal sequencing

Author: Jonas Bergh, Richard Iggo, Tobias Sjöblom, Justine Rudewicz, Elodie Monceau, Hervé Bonnefoi, Nicolas Sevenet, 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, Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Centre de Bioinformatique de Bordeaux (CBIB), CGFB, Department of Oncology, Karolinska Institutet and University Hospital, Manchester Breast Cancer Centre, School of Cancer and Enabling Sciences, University of Manchester and Paterson institute, Medical Oncology Breast Unit Christie Hospital, and Uppsala University
Subjects: Functional assay, MESH: Mutation, DNA Mutational Analysis, Molecular Sequence Data, Mutant, MESH: Genes, p53, MESH: DNA, Neoplasm, Breast Neoplasms, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Saccharomyces cerevisiae, Biology, MESH: Base Sequence, DNA sequencing, Pathology and Forensic Medicine, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Complementary DNA, Humans, MESH: DNA Mutational Analysis, 10. No inequality, 030304 developmental biology, Sanger sequencing, 0303 health sciences, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, DNA, Neoplasm, Genes, p53, Molecular biology, MESH: Saccharomyces cerevisiae, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Yeast, MESH: Artifacts, 030220 oncology & carcinogenesis, Mutation, RNA splicing, symbols, Female, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Artifacts, MESH: Female, MESH: Breast Neoplasms
Abstract: International audience; We have previously tested biopsies from 1469 breast tumours with a p53 functional assay in the context of a prospective clinical trial (EORTC 10994/BIG 1-00). The goal of the trial was to determine whether p53 status could be used to select patients who would benefit from inclusion of taxanes in anthracycline-based chemotherapy. The results of the trial were negative. To test whether this was because the functional assay misclassified the tumours, we have reanalysed two groups of biopsies by Sanger sequencing and Roche 454 next generation sequencing (NGS). Comparison of yeast data with pooled cDNA sequencing data in an initial cohort of 69 biopsies showed that conventional sequencing is insensitive when the mutant p53 content is low. A second cohort of 48 biopsies was used to compare directly the yeast assay with Sanger and NGS technology. The mutant sequence was difficult to detect in sequence chromatograms of pooled cDNA, whereas NGS unequivocally identified mutations in every case classified as mutant by the functional assay. The NGS data showed that small deletions, probably caused by PCR splicing, account for most of the unexplained background in the yeast assay. We conclude that mutation detection techniques that test multiple clones, such as the p53 functional assay and NGS, are more reliable than Sanger sequencing of pooled DNA; that the high p53 mutation rate (44%) seen with the yeast assay in the EORTC 10994/BIG 1-00 trial reflects this high sensitivity; and that NGS with Roche 454 technology could be used to identify the p53 mutations in the remaining tumours previously tested in yeast in the EORTC10994/BIG 1-00 trial.
Published: 2013
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12. STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients

Author: Jean-Claude Capiod, Isabelle Dusanter-Fourt, François Dreyfus, Jacques Delobel, Fabrice Gouilleux, Renate Weber-Nordt, Jean-François Claisse, Bernd Groner, Valérie Gouilleux-Gruart, Lionel Prin, Corinne Desaint, Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), CHU Amiens-Picardie, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Université de Tours
Subjects: MESH: Signal Transduction, MESH: Neoplasm Proteins, Transcription, Genetic, MESH: Base Sequence, Biochemistry, 0302 clinical medicine, hemic and lymphatic diseases, STAT5 Transcription Factor, STAT1, Promoter Regions, Genetic, STAT3, STAT4, STAT5, STAT6, MESH: Aged, 0303 health sciences, Leukemia, biology, Gene Expression Regulation, Leukemic, MESH: STAT3 Transcription Factor, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, DNA, Neoplasm, Hematology, Milk Proteins, Neoplasm Proteins, 3. Good health, DNA-Binding Proteins, STAT1 Transcription Factor, 030220 oncology & carcinogenesis, Acute Disease, MESH: Gene Expression Regulation, Leukemic, Neoplastic Stem Cells, MESH: Acute Disease, Signal Transduction, Adult, STAT3 Transcription Factor, MESH: Milk Proteins, MESH: Trans-Activators, Macromolecular Substances, Molecular Sequence Data, Immunology, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Leukemia, MESH: Promoter Regions, Genetic, Humans, Protein inhibitor of activated STAT, Aged, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Blood Cells, Base Sequence, MESH: Transcription, Genetic, MESH: Blood Cells, MESH: STAT5 Transcription Factor, MESH: Adult, MESH: Macromolecular Substances, Cell Biology, MESH: Neoplastic Stem Cells, Trans-Activators, Cancer research, biology.protein, STAT protein, MESH: STAT1 Transcription Factor, MESH: DNA-Binding Proteins
Abstract: A signal transduction pathway activated by many cytokines has recently been elaborated. The JAK kinases and the signal transducers and activators of transcription (STAT) factors have been found to be essential components. In this report, we describe the presence of constitutively activated STAT factors in peripheral blood cells from patients with acute leukemia. We used oligonucleotide probes from the beta-casein and IRF-1 gene promoters and the ISRE probe to detect STAT proteins in nuclear extracts from acute leukemia cells in bandshift assays. Specific DNA protein complex formation was observed with the probes from the beta-casein and IRF-1 gene promoters, but not with the ISRE oligonucleotide probe, when cell extracts from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were investigated. We used nonradioactive oligonucleotides as competitors to show the specificity of the complex formation. Specific antibodies directed against the individual STAT proteins were used in supershift experiments. STAT5- and STAT1-related factors were detected in ALL and STAT1-, STAT3-, and STAT5-related proteins were present in nuclear cell extracts from AML. Since the cells were not treated with cytokines before the nuclear proteins were extracted, we conclude that these factors are constitutively activated in vivo. It is likely that the constitutive activation of STAT proteins is a part of the events of leukemogenesis.
Published: 1996
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13. [PAIR-gynaecology: multi/interdisciplinary for gynecologic cancer research. Problems needed to be resolved]

Author: Ray-Coquard, Isabelle, Chauvin, Franck, Leblanc, Eric, Caux, Christophe, Hoarau, Hélène, Bonnetain, Franck, Christophe, Véronique, Sastre-Garau, Xavier, Lazennec, Gwendal, Poulain, Laurent, Haie-Meder, Christine, Pujade-Lauraine, Eric, Salzet, Michel, Deutsch, Eric, Devouassoux, Mojgan, Penault Llorca, Frédérique, Lecuru, Fabrice, Taieb, Sophie, Arveux, Patrick, Theillet, Charles, Joly, Florence, Département d'Oncologie Médicale, 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Department of Surgery, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département de Biologie des Tumeurs, Institut Curie [Paris], Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Régional d'Etudes sur le CANcer (GRECAN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-IFR146, Service d'Oncologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroimmunologie des annélides (NA), Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Hopitaux de Paris, Université Paris Descartes - Paris 5 (UPD5), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Etienne, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, 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]-Université Claude Bernard Lyon 1 (UCBL), IFR146-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), 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), CRLCC Oscar Lambret, 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)-Université Claude Bernard Lyon 1 (UCBL), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut Curie, IFR146-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Hôtel-Dieu [Paris]-AP-HP, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Centre Léon Bérard [Lyon]-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Santé-Individu-Société 'SIS', 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 ), 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]-Université Claude Bernard Lyon 1 ( UCBL ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), INSTITUT CURIE, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Groupe Régional d'Etudes sur le CANcer ( GRECAN ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ) -IFR146, Université Paris Descartes - Paris 5 ( UPD5 ) -Hôpital Hôtel-Dieu [Paris]-AP-HP, Neuroimmunologie des annélides ( NA ), Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Institut de recherche en cancérologie de Montpellier ( IRCM - U896 Inserm - UM1 ), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ), Université Claude Bernard Lyon 1 ( UCBL ), 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 ), 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 ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut de recherche en cancérologie de Montpellier ( IRCM ), and Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM )
Subjects: Biomedical Research, Uterine Cervical Neoplasms, MESH : Early Detection of Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genital Neoplasms, Female, Risk Factors, MESH : Fertility, MESH: Risk Factors, MESH : Tumor Markers, Biological, MESH : Female, Immunologic Surveillance, Early Detection of Cancer, Ovarian Neoplasms, DNA, Neoplasm, MESH : Risk Factors, MESH: Uterine Cervical Neoplasms, MESH: Ovarian Neoplasms, MESH: Sexuality, MESH : Sexuality, Female, France, MESH : DNA, Neoplasm, MESH: Endometrial Neoplasms, Sexuality, MESH : Biomedical Research, Genital Neoplasms, Female, MESH : Uterine Cervical Neoplasms, MESH : Genital Neoplasms, Female, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, Humans, MESH: Early Detection of Cancer, MESH : France, MESH: Immunologic Surveillance, MESH: Humans, MESH : Ovarian Neoplasms, MESH: Biomedical Research, MESH : Humans, MESH: Quality of Life, MESH: Fertility, MESH : Quality of Life, Endometrial Neoplasms, MESH: France, MicroRNAs, MESH : MicroRNAs, Fertility, MESH : Endometrial Neoplasms, MESH: Tumor Markers, Biological, Quality of Life, MESH : Immunologic Surveillance, MESH: MicroRNAs, MESH: Female
Abstract: International audience; Each year, 13,000 newly gynecologic cancers are diagnosed in France. Gynecologic cancers were specifically heterogeneous (localisations, histologic subgroups, age class, etc). This work was delineated for a national call dedicated to gynecologic cancers. This review reports the major needs in terms of scientific research dedicated to gynecologic cancers in the biologic, epidemiology, human and sociologic fields. For example, medico-economic strategies adapted to ethnosociologic context, specifically for cervix cancer, took important part of the epidemiologic research. Impact of gynecologic cancer in terms of symptoms and late effects, quality of life after treatments and fertility needs to be specifically explored. For fundamental research, molecular characterisation, biologic markers, impact of immunology and genetics represent the major part of the field need to be explored. Finally, therapeutic and diagnosis innovations, optimization of treatments strategies and development of predictive models in order to perform individual prediction taking into account several risk factors (clinical and molecular) to offer help in management of gynecologic cancers are required.
Published: 2012
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14. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation

Author: Sylvie Salenave, Jessica Zucman-Rossi, Emmanuelle Jeannot, Gabrielle Couchy, Philippe Chanson, Paulette Bioulac-Sage, Jean-Charles Nault, Charles Balabaud, Marie-José Redon, Camilla Pilati, Sophie Prevot, Marie-Christine Saint-Paul, Philippe Labrune, Jeanne Tran Van Nhieu, Anne de Muret, Monique Fabre, Jean-Yves Scoazec, Catherine Buffet, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pôle Digestif, Hôpital Archet 2 [Nice] (CHU), Service d'hépato-gastro-entérologie, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et de Cytologie Pathologiques [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Antoine-Béclère, Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie [Béclère], 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]-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)-Anipath, UFR Médecine Lyon-RTH Laennec-UFR Médecine Lyon-RTH Laennec, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service d'Endocrinologie et Maladies de la reproduction, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine-Béclère, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), 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)-Université Claude Bernard Lyon 1 (UCBL), 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)-Anipath, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Hôpital Archet 2 [Nice] ( CHU ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine-Béclère, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, 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 ) -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 ) -Anipath, Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre
Subjects: Male, MESH: Signal Transduction, MESH : Liver Neoplasms, MESH : GTP-Binding Protein alpha Subunits, Gs, DNA Mutational Analysis, MESH : Aged, MESH : Models, Biological, Gene mutation, MESH: Base Sequence, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Adenoma, Liver Cell, 0302 clinical medicine, MESH: Liver Neoplasms, MESH : STAT3 Transcription Factor, GTP-Binding Protein alpha Subunits, Gs, MESH : Female, MESH: DNA Mutational Analysis, MESH: Carcinoma, Hepatocellular, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Liver Neoplasms, MESH: STAT3 Transcription Factor, DNA, Neoplasm, MESH : Adult, Middle Aged, 3. Good health, HNF1A, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Female, MESH : DNA, Neoplasm, MESH : Mutation, Signal Transduction, MESH : Carcinoma, Hepatocellular, Adult, STAT3 Transcription Factor, musculoskeletal diseases, Carcinoma, Hepatocellular, MESH: Mutation, MESH: Fibrous Dysplasia, Polyostotic, MESH : Male, MESH : Fibrous Dysplasia, Polyostotic, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, Fibrous Dysplasia, Polyostotic, Models, Biological, Adenoma, Liver Cell, 03 medical and health sciences, MESH : Adenoma, Liver Cell, Chromogranins, medicine, GNAS complex locus, Humans, MESH : Middle Aged, Aged, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, Base Sequence, Hepatology, Oncogene, MESH : Humans, MESH: Models, Biological, MESH: Adult, Hepatocellular adenoma, MESH: GTP-Binding Protein alpha Subunits, Gs, medicine.disease, MESH: Male, Mutation, Inflammatory Hepatocellular Adenoma, biology.protein, Cancer research, MESH : Base Sequence, Carcinogenesis, MESH: Female
Abstract: Background & Aims Mosaic G-protein alpha-subunit ( GNAS )-activating mutations are responsible for the McCune–Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis. Methods GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines. Results A somatic GNAS -activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A , CTNNB1 , and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS -mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS -mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation. Conclusions We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS -activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.
Published: 2012
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15. A subset of chronic lymphocytic leukemia patients display reduced levels of PARP1 expression coupled with a defective irradiation-induced apoptosis

Author: Valeria Di Maio, Simona Santangelo, Francesca Romana Mauro, Simona Tavolaro, Paola Caiafa, Nadia Peragine, Maria Rosaria Ricciardi, Anna Guarini, Robin Foà, Anna Reale, Marilisa Marinelli, Sabina Chiaretti, Ilaria Del Giudice, Maria Giulia Bacalini, Bacalini, Maria Giulia, Tavolaro, Simona, Peragine, Nadia, Marinelli, Marilisa, Santangelo, Simona, del Giudice, Ilaria, Mauro, Francesca Romana, di Maio, Valeria, Ricciardi, Maria Rosaria, Caiafa, Paola, Chiaretti, Sabina, Foà, Robin, Guarini, Anna, Reale, Anna, Department of Cellular Biotechnologies and Haematology, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Division of Hematology, Department of Cellular Biotechnologies and Hematology, and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]
Subjects: MESH: Neoplasm Proteins, Cancer Research, Microarray, Chronic lymphocytic leukemia, MESH: Genes, p53, Immunoglobulin Variable Region, Poly (ADP-Ribose) Polymerase-1, MESH: Immunoglobulin Variable Region, Apoptosis, 0302 clinical medicine, PARP1, Tumor Cells, Cultured, RNA, Neoplasm, MESH: Tumor Suppressor Protein p53, MESH: Leukemia, Lymphocytic, Chronic, B-Cell, Poly(ADP-ribose) Polymerase, MESH: Treatment Outcome, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Apoptosis Regulatory Protein, medicine.diagnostic_test, Gene Expression Regulation, Leukemic, Gamma Ray, Hematology, DNA, Neoplasm, Chronic lymphocytic leukemia (CLL), 3. Good health, Neoplasm Proteins, Real-time polymerase chain reaction, Treatment Outcome, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, MESH: Gene Expression Regulation, Leukemic, Poly(ADP-ribose) Polymerases, Immunoglobulin Heavy Chains, MESH: Immunoglobulin Heavy Chains, Human, MESH: Mutation, Immunoglobulin Heavy Chain, Poly ADP ribose polymerase, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, PARP-1, Biology, Neoplasm Protein, 03 medical and health sciences, Genetic, Western blot, Genetics, medicine, Humans, MESH: Tumor Cells, Cultured, RNA, Messenger, Molecular Biology, MESH: RNA, Messenger, 030304 developmental biology, MESH: DNA Damage, apoptosis, MESH: Humans, MESH: Apoptosis Regulatory Proteins, Oligonucleotide Array Sequence Analysi, Microarray analysis techniques, MESH: Apoptosis, MESH: Poly(ADP-ribose) Polymerases, Apoptosi, Cell Biology, MESH: Gamma Rays, Repressor Protein, MESH: RNA, Neoplasm, medicine.disease, Genes, p53, Leukemia, Lymphocytic, Chronic, B-Cell, Repressor Proteins, Gamma Rays, MESH: Oligonucleotide Array Sequence Analysis, Mutation, Cancer research, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, DNA Damage
Abstract: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by defects in the DNA damage response and apoptosis. Among the factors involved in these pathways, we focused on the enzyme poly(ADP-ribose) polymerase 1 (PARP1) and on its substrate Che-1 by evaluating their basal expression and functional changes upon irradiation (IR). Microarray experiments were performed on 98 untreated CLL cases. Next, freshly isolated primary cells from 21 untreated patients were analyzed for invitro response to irradiation through Western blot, PARP activity assay, Annexin-V analysis, and PARP1 basal expression by quantitative polymerase chain reaction. Microarray analysis showed that PARP1 and CHE1 were constitutively expressed in CLL and had a high degree of correlation with each other and with TP53. PARP1 and TP53 downmodulation was associated with worse clinical outcomes, especially in TP53-mutated cases. Next, CLL samples from 21 untreated patients were classified as responders and nonresponders based on IR-induced PARP1 cleavage. Notably, while responder samples were characterized by Che-1 and p53 induction at 8 hours and reduction at 24 hours post-IR, nonresponders included both samples with p53 dysfunctions and cases with a normal IR-induced Che-1 and/or p53 response. Finally, we observed that PARP1 was downregulated in nonresponder vs responder samples and that its basal expression was positively correlated with PARP1 cleavage after IR. In conclusion, we showed that reduced expression of PARP1 is associated with an impairment of CLL responsiveness to cell death. Â© 2012 ISEH - Society for Hematology and Stem Cells.
Published: 2011
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16. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas

Author: Pilati, Camilla, Amessou, Mohamed, Bihl, Michel, Balabaud, Charles, Nhieu, Jeanne Tran Van, Paradis, Valérie, Nault, Jean Charles, Izard, Tina, Bioulac-Sage, Paulette, Couchy, Gabrielle, Poussin, Karine, Zucman-Rossi, Jessica, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Pathologie [Clichy], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Cancer Biology, The Scripps Research Institute [La Jolla, San Diego], Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Hépato-Gastro Entérologie et Oncologie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by the association pour la recherche Contre le Cancer (ARC, grant n°3194), Inserm (Réseaux de recherche clinique et réseaux de recherche en santé des populations), Collection Nationale des Carcinomes Hépatocellulaires, the Ligue Nationale Contre le Cancer ('Cartes d'identité des tumeurs' program) and the BioIntelligence collaborative program. C.P., M.A. and J-C.N. are supported by a fellowship from the MENRT, Inca and ARC, respectively. T.I. is supported by the National Institutes of Health grants GM071596, AI055894, and AI067949., Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, The Scripps Research Institute, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
Subjects: MESH: Signal Transduction, MESH: Mutation, MESH: Cell Line, Tumor, MESH: Protein Structure, Quaternary, MESH: DNA, Neoplasm, MESH: Active Transport, Cell Nucleus, MESH: Base Sequence, IFN, HNF1A, MESH: Tyrosine, STAT3, gp130, MESH: Adenoma, Liver Cell, MESH: Mutant Proteins, MESH: Liver Neoplasms, MESH: RNA, Small Interfering, CTNNB1, SOCS3, MESH: Carcinoma, Hepatocellular, MESH: Aged, IL-6, MESH: Humans, MESH: Middle Aged, MESH: Phosphorylation, MESH: STAT3 Transcription Factor, beta-catenin, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Interleukin-6, SAA, MESH: Male, JAK1, MESH: Cytokine Receptor gp130, JAK2, MESH: src-Family Kinases, MESH: Dimerization, CRP, IL6ST, MESH: Female, MESH: Models, Molecular, Src
Abstract: International audience; Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6-induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6-STAT3 pathway in benign hepatocellular tumorigenesis.
Published: 2011
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17. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas.: Activating STAT3 mutations in hepatocellular adenoma

Author: Pilati, Camilla, Amessou, Mohamed, Bihl, Michel, Balabaud, Charles, Nhieu, Jeanne Tran Van, Paradis, Valérie, Nault, Jean Charles, Izard, Tina, Bioulac-Sage, Paulette, Couchy, Gabrielle, Poussin, Karine, Zucman-Rossi, Jessica, Zucman-Rossi, Jessica, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Pathologie [Clichy], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Cancer Biology, The Scripps Research Institute [La Jolla, San Diego], Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Hépato-Gastro Entérologie et Oncologie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and This work was supported by the association pour la recherche Contre le Cancer (ARC, grant n°3194), Inserm (Réseaux de recherche clinique et réseaux de recherche en santé des populations), Collection Nationale des Carcinomes Hépatocellulaires, the Ligue Nationale Contre le Cancer ('Cartes d'identité des tumeurs' program) and the BioIntelligence collaborative program. C.P., M.A. and J-C.N. are supported by a fellowship from the MENRT, Inca and ARC, respectively. T.I. is supported by the National Institutes of Health grants GM071596, AI055894, and AI067949.
Subjects: MESH: Signal Transduction, MESH: Mutation, MESH: Cell Line, Tumor, MESH: Protein Structure, Quaternary, MESH: DNA, Neoplasm, MESH: Active Transport, Cell Nucleus, MESH: Base Sequence, IFN, HNF1A, MESH: Tyrosine, STAT3, gp130, MESH: Adenoma, Liver Cell, MESH: Mutant Proteins, MESH: Liver Neoplasms, MESH: RNA, Small Interfering, CTNNB1, SOCS3, MESH: Carcinoma, Hepatocellular, MESH: Aged, IL-6, MESH: Humans, MESH: Middle Aged, MESH: Phosphorylation, MESH: STAT3 Transcription Factor, beta-catenin, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Interleukin-6, SAA, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, JAK1, MESH: Cytokine Receptor gp130, JAK2, MESH: src-Family Kinases, MESH: Dimerization, CRP, IL6ST, MESH: Female, MESH: Models, Molecular, Src
Abstract: International audience; Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6-induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6-STAT3 pathway in benign hepatocellular tumorigenesis.
Published: 2011
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18. TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy

Author: Gaëlle Bougeard, F. Boissière, Jean-Jacques Tuech, J.-C. Sabourin, Frédéric Bibeau, Marc Ychou, David Tougeron, Françoise Charbonnier, Pierre Michel, F. Le Pessot, Aude Lamy, Thierry Frebourg, F. Di Fiore, Alice Oden-Gangloff, F. Blanchard, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire Ecologie Fonctionnelle et Environnement (LEFE), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Neurobiologie des réseaux sensorimoteurs (NRS (U7060)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences du Génie Chimique (LSGC), Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cancer de Montpellier (ICM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Bougeard, Gaëlle, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), and Hôpital Lapeyronie [Montpellier] (CHU)
Subjects: Male, Cancer Research, endocrine system diseases, Colorectal cancer, medicine.medical_treatment, Cetuximab, medicine.disease_cause, Targeted therapy, Metastasis, MESH: Dose-Response Relationship, Drug, MESH: Antibodies, Monoclonal, MESH: Genotype, 0302 clinical medicine, MESH: Cetuximab, TP53, Neoplasm Metastasis, MESH: Tumor Suppressor Protein p53, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Colerectal cancer, Antibodies, Monoclonal, DNA, Neoplasm, Exons, Middle Aged, targeted therapy, MESH: Amino Acid Substitution, 3. Good health, Exact test, Oncology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Disease Progression, Female, KRAS, Colorectal Neoplasms, MESH: ras Proteins, medicine.drug, MESH: Mutation, Genotype, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, colorectal cancer, Antibodies, Monoclonal, Humanized, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Proto-Oncogene Proteins p21(ras), [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Proto-Oncogene Proteins, medicine, Humans, neoplasms, Molecular Diagnostics, 030304 developmental biology, Aged, molecular marker, Chemotherapy, MESH: Humans, Dose-Response Relationship, Drug, business.industry, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, MESH: Neoplasm Metastasis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, digestive system diseases, MESH: Proto-Oncogene Proteins, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amino Acid Substitution, MESH: Antibodies, Monoclonal, Humanized, Mutation, Cancer research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, ras Proteins, MESH: Antineoplastic Agents, Tumor Suppressor Protein p53, business, MESH: Exons, MESH: Female, MESH: Colorectal Neoplasms
Abstract: International audience; Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan-Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.
Published: 2009
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19. p53 dependent cell-cycle arrest triggered by chemotherapy in xenografted breast tumors

Author: Mariana Varna, Jacqueline Lehmann-Che, Elisabeth Turpin, Elizabetha Marangoni, Morad El-Bouchtaoui, Marion Jeanne, Carmen Grigoriu, Philippe Ratajczak, Christophe Leboeuf, Louis-François Plassa, Irmine Ferreira, Marie-France Poupon, Anne Janin, Hugues de Thé, Philippe Bertheau, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pathologie et virologie moléculaire (PVM (UMR_7151)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département Inserm Transfert, Institut Curie [Paris], Service d'anatomo-pathologie [Paris], Ratajczak, Philippe, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: Cancer Research, Cell cycle checkpoint, endocrine system diseases, DNA Mutational Analysis, MESH: Genes, p53, MESH: Cell Cycle, Mice, MESH: Mammary Neoplasms, Animal, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, MESH: Animals, MESH: DNA Mutational Analysis, MESH: Tumor Suppressor Protein p53, Mitotic catastrophe, Cellular Senescence, 0303 health sciences, Cell Cycle, DNA, Neoplasm, Cell cycle, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, MESH: Cell Aging, 030220 oncology & carcinogenesis, Senescence, medicine.medical_specialty, MESH: Mutation, Tumor suppressor gene, MESH: DNA, Neoplasm, Antineoplastic Agents, Breast Neoplasms, Mammary Neoplasms, Animal, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Epirubicin, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Animals, Humans, Mitosis, Cyclophosphamide, neoplasms, MESH: Mice, 030304 developmental biology, Epirubicin, MESH: Humans, MESH: Cyclophosphamide, medicine.disease, Genes, p53, Transplantation, Endocrinology, Mutation, Cancer research, MESH: Antineoplastic Agents, Tumor Suppressor Protein p53, Neoplasm Transplantation, MESH: Neoplasm Transplantation, MESH: Breast Neoplasms
Abstract: International audience; The major long-term prognostic factor for breast cancer patients treated by first-line chemotherapy is response to treatment. We have previously shown that complete responses to high doses epirubicin-cyclophosphamide were observed only in human tumors bearing a TP53 mutation. Three xenografted human breast tumors, 2 of them with a TP53 mutation and one of them without, were studied for their immediate response to this drug association. Cell cycle, cellular senescence and cell death were characterized and quantified on tissue section before and after treatment. The TP53 wild-type tumor showed a strong early induction of senescence-like phenotype with overexpression of SA-beta-gal and p21(CIP1). In contrast both TP53 mutated tumors showed no sign of cell cycle arrest or senescence. Conversely, abnormal mitoses strongly increased, only in TP53 mutated tumors. Thus, in these in vivo models, epirubicin-cyclophosphamide treatment induces senescence-like features in TP53 wild-type tumor, likely accounting for cell cycle arrest and subsequent resistance to treatment. Conversely in TP53 mutated tumors, chemotherapy induces mitotic catastrophe and tumor death, accounting for complete response to this association exclusively in patients with TP53 mutated tumors.
Published: 2009
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20. Overall genomic pattern is a predictor of outcome in neuroblastoma

Author: Jérôme Couturier, Dominique Plantaz, Alexander Valent, Agnès Ribeiro, Dominique Valteau-Couanet, Michel Peuchmaur, Caroline Thomas, Evi Michels, Véronique Mosseri, Isabelle Janoueix-Lerosey, Jean Michon, Delphine Lequin, Gudrun Schleiermacher, Hervé Rubie, Olivier Delattre, Angelika Eggert, Raphael Rousseau, Frank Speleman, Joëlle Vermeulen, Valérie Combaret, 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 ), Département de Pédiatrie, INSTITUT CURIE, Center for Medical Genetics [Ghent], Ghent University Hospital, Service de biostatistique ( IC10213 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Unité de génétique somatique, Unité de Cytogénétique, Service d'anatomie et de cytologie pathologique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy ( IGR ), Service Hématologie Infantile, CHU Grenoble, Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service Hémato-Oncologie Infantile, Laboratoire d'Oncologie Moléculaire, Centre Léon Bérard [Lyon], Department of Paediatric Oncology and Haematology, University Children's Hospital of Essen, Département d'oncologie pédiatrique, Supported by grants from the Institut National de la Sante´ et de la Recherche Me´ dicale and the Ligue Nationale contre le Cancer (Equipe labellise´ e). Construction of the BAC/PAC array was supported by grants from the Carte d'Identite´ des Tumeurs/Program of the Ligue Nationale Contre le Cancer. Belgian array-CGH results were obtained by support of the Stichting tegen Kanker and Specific Targeted Research Project. E.M. is supported by the concerted research fund (GOA, No. 12051203). J.V. is supported by the Belgian Kids' Fund., Janoueix-Lerosey, Isabelle, 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], Service de biostatistique (IC10213), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Gustave Roussy (IGR), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], and Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Oncology, Cancer Research, Pathology, Genes, myc, Medizin, MESH: Gene Amplification, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Proportional Hazards Models, Neuroblastoma, 0302 clinical medicine, MESH : Tumor Markers, Biological, Copy-number variation, MESH : Comparative Genomic Hybridization, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Comparative Genomic Hybridization, MESH : Prognosis, MESH: Genomic Instability, MESH : Gene Amplification, MESH : Infant, MESH: Follow-Up Studies, DNA, Neoplasm, Prognosis, MESH: Infant, MESH : Oligonucleotide Array Sequence Analysis, MESH : Genes, myc, 030220 oncology & carcinogenesis, MESH: Survival Analysis, MESH : DNA, Neoplasm, medicine.medical_specialty, Copy number analysis, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, MESH: Multivariate Analysis, Genomic Instability, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Biomarkers, Tumor, Humans, Clinical significance, Survival analysis, MESH: Genes, myc, 030304 developmental biology, Proportional Hazards Models, MESH: Humans, business.industry, Proportional hazards model, MESH : Humans, Gene Amplification, Cancer, MESH : Multivariate Analysis, Infant, MESH : Follow-Up Studies, medicine.disease, MESH : Proportional Hazards Models, MESH: Neuroblastoma, Survival Analysis, MESH: Comparative Genomic Hybridization, MESH: Oligonucleotide Array Sequence Analysis, MESH: Tumor Markers, Biological, Multivariate Analysis, MESH : Neuroblastoma, MESH : Survival Analysis, business, MESH : Genomic Instability, Comparative genomic hybridization, Follow-Up Studies
Abstract: Purpose For a comprehensive overview of the genetic alterations of neuroblastoma, their association and clinical significance, we conducted a whole-genome DNA copy number analysis. Patients and Methods A series of 493 neuroblastoma (NB) samples was investigated by array-based comparative genomic hybridization in two consecutive steps (224, then 269 patients). Results Genomic analysis identified several types of profiles. Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. Patients with both numerical and segmental abnormalities clearly shared the higher risk of relapse of segmental-only patients. In a multivariate analysis, taking into account the genomic profile, but also previously described individual genetic and clinical markers with prognostic significance, the presence of segmental alterations with (HR, 7.3; 95% CI, 3.7 to 14.5; P < .001) or without MYCN amplification (HR, 4.5; 95% CI, 2.4 to 8.4; P < .001) was the strongest predictor of relapse; the other significant variables were age older than 18 months (HR, 1.8; 95% CI, 1.2 to 2.8; P = .004) and stage 4 (HR, 1.8; 95% CI, 1.2 to 2.7; P = .005). Finally, within tumors showing segmental alterations, stage 4, age, MYCN amplification, 1p and 11q deletions, and 1q gain were independent predictors of decreased overall survival. Conclusion The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.
Published: 2009
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21. Episomal amplification of MYCN in a case of medulloblastoma

Author: Fanny Burel-Vandenbos, Clelia Tiziana Storlazzi, Cecilia Surace, Domenico Trombetta, Florence Pedeutour, Mariano Rocchi, Department of Genetics and Microbiology, Univ. Bari, Università degli studi di Bari Aldo Moro (UNIBA), Laboratory of Cytogenetics and Molecular Genetics, IRCCS, Laboratory of Solid Tumors Genetics, Nice University Hospital, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Department of Pathology
Subjects: Male, MESH: Gene Amplification, 0302 clinical medicine, Gene duplication, MESH: In Situ Hybridization, Fluorescence, In Situ Hybridization, Fluorescence, Oncogene Proteins, 0303 health sciences, N-Myc Proto-Oncogene Protein, medicine.diagnostic_test, Nuclear Proteins, General Medicine, DNA, Neoplasm, Prognosis, Primary tumor, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Plasmids, Adolescent, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Prognosis, Pathology and Forensic Medicine, 03 medical and health sciences, MESH: Oncogene Proteins, MESH: Plasmids, Neuroblastoma, medicine, Humans, Cerebellar Neoplasms, Molecular Biology, neoplasms, MESH: Cerebellar Neoplasms, 030304 developmental biology, MESH: Medulloblastoma, Medulloblastoma, MESH: Adolescent, MESH: Humans, Oncogene, Gene Amplification, Cell Biology, medicine.disease, Molecular biology, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Nuclear Proteins, Fluorescence in situ hybridization
Abstract: Gene amplification, in the form of double minutes (dmin) and/or homogeneously staining regions (hsr), is frequently associated with tumor development. A well-known example is neuroblastoma for which MYCN gene (v-myc myelocytomatosis viral-related oncogene) amplification has a relevant prognostic significance. A third cryptic form of amplification, cytogenetically invisible and composed of episomes, has been also described, but it is very rarely seen in primary tumors. In this paper, we report on MYCN amplification, in the form of episomes, in a case of medulloblastoma. Detailed fluorescence in situ hybridization and real-time quantitative polymerase chain reaction analyses revealed an amplified genomic segment of approximately 590 kb containing only the genes MYCN and N-cym (v-myc myelocytomatosis viral-related oncogene, neuroblastoma-derived opposite strand). To the best of our knowledge, this is the first report of a solid primary tumor showing MYCN amplification in the form of episomes.
Published: 2008
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22. T-cell lymphoid aggregates in bone marrow after rituximab therapy for B-cell follicular lymphoma: a marker of therapeutic efficacy?

Author: Diane Damotte, Anne Moreau, Sylvie Caulet-Maugendre, Marie C. Béné, Pascale Cornillet Lefebvre, Martine Patey, Gilles Salles, Marie Christine Rousselet, Jean François Rossi, Pierre Raynaud, Charles Foussard, Antoine Martin, Valérie Costes, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service d'hématologie clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Service d'hématologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel Dieu, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Haematology, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Département de Pathologie Cellulaire et Tissulaire, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Immunologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de chirurgie thoracique et d'anatomopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Hôtel Dieu, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Rhumatologie, Hôpital de St Brieuc, university hospital, University Hospital, Université de Rennes (UR), Université de Rennes (UR)-Hôpital Pontchaillou, École normale supérieure de Lyon (ENS de 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), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Hôtel Dieu
Subjects: Male, Pathology, T-Lymphocytes, T-cell infiltration, Follicular lymphoma, Translocation, Genetic, MESH: Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, MESH: Lymphoma, Follicular, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Reverse Transcriptase Polymerase Chain Reaction, Lymphoma, Follicular, MESH: Treatment Outcome, Gene Rearrangement, CD20, MESH: Aged, 0303 health sciences, MESH: Middle Aged, biology, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, Anti-CD20 monoclonal antibodies, Antibodies, Monoclonal, DNA, Neoplasm, Middle Aged, MESH: Translocation, Genetic, 3. Good health, Survival Rate, Treatment Outcome, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Female, Rituximab, MESH: Bone Marrow, medicine.drug, Adult, medicine.medical_specialty, Bcl2, Lymphoma, B-Cell, MESH: Survival Rate, MESH: Gene Rearrangement, MESH: DNA, Neoplasm, Antineoplastic Agents, Pathology and Forensic Medicine, 03 medical and health sciences, Biopsy, medicine, Humans, Bone marrow, B cell, Aged, 030304 developmental biology, MESH: Lymphoma, B-Cell, Chromosomes, Human, Pair 14, MESH: Humans, business.industry, MESH: Adult, medicine.disease, MESH: Male, Lymphoma, MESH: T-Lymphocytes, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Antibodies, Monoclonal, Murine-Derived, biology.protein, MESH: Antineoplastic Agents, MESH: Chromosomes, Human, Pair 14, CD5, Chromosomes, Human, Pair 18, business, MESH: Chromosomes, Human, Pair 18, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Rituximab, an anti-CD20 monoclonal antibody, is widely used in the treatment of B-cell lymphoma. Some reports have outlined histologic modifications in bone marrow specimens from patients treated with this antibody, notably the presence of CD3(+) lymphoid aggregates morphologically mimicking residual lymphoma. To gain insight into the significance of such infiltrates, serial BM trephines obtained in 39 patients with B-cell follicular lymphoma treated by rituximab and enrolled in the GOELAMS-GELA intergroup FL2000 protocol were reexamined. The 39 patients were 22 women and 17 men with a median age of 50 years (range, 29-75 years). All pretreatment bone marrow biopsies showed CD20(+) lymphomatous cells. A second biopsy was obtained between 30 and 100 days after the last rituximab injection: 19 (48%) were morphologically diagnosed as negative (no lymphoid infiltrates or only minor lymphoid aggregates) and 20 (51%) as positive because of persistent lymphoid nodules. After immunohistochemical analysis, 13 (33%) cases were reinterpreted as false-positive because of the complete absence of CD20(+) cells, with the lymphoid nodules consisting of CD3(+) and CD5(+) T cells. Most of them also expressed CD4(+), whereas only a few CD8(+) cells were present. Among these 13 false-positive cases, 12 were BCL2-IGH polymerase chain reaction-negative in the bone marrow aspirate at the time of biopsy. The 13th case turned out to be negative in the 18th-month bone marrow aspirate. In all of these cases, lymphoid aggregates had disappeared on bone marrow biopsies performed 18 months after treatment. After a mean follow-up of 4.5 years, 9 of 13 patients were in remission as compared with only 2 among the 7 patients with postrituximab persistent CD20(+) lymphomatous cells. There was no statistically significant difference between this false-positive group of patients and that with negative postrituximab bone marrow regarding sex, age, medullar involvement pattern before treatment, delay between rituximab treatment, and molecular status. Interestingly, we noted a more favorable outcome (70% versus 52% remission) for the false-positive cases, suggesting that these T-cell reactions could be the hallmark of specific antitumoral immunity after rituximab treatment and should be properly investigated.
Published: 2008
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23. TP53 codon 72 polymorphism, p53 expression, and 1p/19q status in oligodendroglial tumors

Author: Soufiane El Hallani, Blandine Boisselier, Florence Laigle-Donadey, Mathieu P Rodero, Catherine Carpentier, Ahmed Idbaih, Emmanuelle Crinière, Marc Sanson, Yannick Marie, François Ducray, Khê Hoang-Xuan, Jean-Yves Delattre, Sophie Paris, Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie cellulaire et tissulaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Idbaih, Ahmed, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Male, Cancer Research, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Immunoenzyme Techniques, MESH: Glioma, MESH: Genotype, 0302 clinical medicine, Genotype, Oligodendroglial Tumor, MESH: Tumor Suppressor Protein p53, ComputingMilieux_MISCELLANEOUS, MESH: Aged, MESH: Middle Aged, MESH: Codon, Brain Neoplasms, Astrocytoma, DNA, Neoplasm, Glioma, Middle Aged, Prognosis, MESH: Case-Control Studies, Survival Rate, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Adult, MESH: Survival Rate, MESH: Chromosomes, Human, Pair 1, Oligodendroglioma, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Biology, MESH: Prognosis, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, SNP, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Codon, MESH: Immunoenzyme Techniques, MESH: Oligodendroglioma, Molecular Biology, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, Case-control study, MESH: Adult, medicine.disease, Molecular biology, MESH: Male, MESH: Astrocytoma, Case-Control Studies, MESH: Microsatellite Repeats, Tumor Suppressor Protein p53, MESH: Female, 030217 neurology & neurosurgery, Microsatellite Repeats
Abstract: International audience; The functional single-nucleotide polymorphism (SNP) in codon 72 of TP53 has been shown to be both a risk factor and a prognostic biomarker in various cancers. Such results were also reported in brain tumors, notably in astrocytomas. This SNP has never been precisely investigated in oligodendroglial tumors. We retrospectively analyzed blood samples of 275 oligodendroglial tumor patients for the TP53 codon 72 polymorphism and compared them with a series of 144 healthy controls. Arg/Arg, Arg/Pro, and Pro/Pro genotypes were found in 54.2 versus 60.4%, 39.3 versus 34.0%, and 7.3 versus 5.6% of patients and controls, respectively. This suggests no association between oligodendroglial tumors and the SNP in codon 72 of TP53. Similarly, no correlation was found among the TP53 codon 72 polymorphism and prognosis, p53 expression, and chromosomes 1p and 19q status.
Published: 2007
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24. GATA-1 is essential in EGF-mediated induction of nucleotide excision repair activity and ERCC1 expression through ERK2 in human hepatoma cells

Author: Georges Baffet, Lise O. Andrieux, André Guillouzo, Alain Fautrel, Anne Bessard, Sophie Langouët, Détoxication et réparation tissulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plate-forme d'histopathologie, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Régulations des équilibres fonctionnels du foie normal et pathologique, Université de Rennes (UNIV-RENNES), Institut National de la Santé et de la Recherche Médicale, Association pour la Recherche sur le Cancer (ARC), Ligue contre le Cancer-Comité d'Ille et Vilaine, Fondation Langlois, Ministère délégué à la Recherche, Région Bretagne/INSERM, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: MAPK/ERK pathway, Cancer Research, MESH: Epidermal Growth Factor, Carcinoma, Hepatocellular, DNA Repair, MAP Kinase Signaling System, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, GATA-1, Small hairpin RNA, 03 medical and health sciences, 0302 clinical medicine, Epidermal growth factor, MESH: Liver Neoplasms, MESH: Endonucleases, Tumor Cells, Cultured, Humans, GATA1 Transcription Factor, MESH: Tumor Cells, Cultured, Protein kinase A, MESH: Carcinoma, Hepatocellular, Transcription factor, PI3K/AKT/mTOR pathway, 030304 developmental biology, MESH: GATA1 Transcription Factor, MESH: DNA Repair, Mitogen-Activated Protein Kinase 1, 0303 health sciences, MESH: Humans, Epidermal Growth Factor, Kinase, MESH: MAP Kinase Signaling System, Liver Neoplasms, human hepatocytes, DNA, Neoplasm, nucleotide excision repair, Endonucleases, Molecular biology, MAPK, 3. Good health, DNA-Binding Proteins, Oncology, 030220 oncology & carcinogenesis, Signal transduction, ERCC1, MESH: DNA-Binding Proteins, MESH: Mitogen-Activated Protein Kinase 1
Abstract: The nucleotide excision repair (NER) pathway and its leading gene excision-repair cross-complementary 1 (ERCC1) have been shown to be up-regulated in hepatocellular carcinomas even in the absence of treatment with chemotherapeutics. The aim of this study was to determine the mechanism involved in NER regulation during the liver cell growth observed in hepatocellular carcinoma. Both NER activity and ERCC1 expression were increased after exposure to the epidermal growth factor (EGF) in cultured normal and tumoral human hepatocytes. These increases correlated with the activation of the kinase signaling pathway mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK that is known to be a key regulator in the G1 phase of the hepatocyte cell cycle. Moreover, EGF-mediated activation of ERCC1 was specifically inhibited by either the addition of U0126, a MEK/ERK inhibitor or small interfering RNA-mediated knockdown of ERK2. Basal expression of ERCC1 was decreased in the presence of the phosphoinositide-3-kinase (PI3K) inhibitor and small hairpin RNA (shRNA) against the PI3K pathway kinase FKBP12-rapamycin-associated protein or mammalian target of rapamycin. Transient transfection of human hepatocytes with constructs containing different sizes of the 5′-flanking region of the ERCC1 gene upstream of the luciferase reporter gene showed an increase in luciferase activity in EGF-treated cells, which correlated with the presence of the nuclear transcription factor GATA-1 recognition sequence. The recruitment of GATA-1 was confirmed by chromatin immunoprecipitation assay. In conclusion, these results represent the first demonstration of an up-regulation of NER and ERCC1 in EGF-stimulated proliferating hepatocytes. The transcription factor GATA-1 plays an essential role in the induction of ERCC1 through the mitogen-activated protein kinase (MAPK) pathway, whereas the PI3K signaling pathway contributes to ERCC1 basal expression. [Cancer Res 2007;67(5):2114–23]
Published: 2007
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25. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets

Author: Boyault, Sandrine, Rickman, David, de Reyniès, Aurélien, Balabaud, Charles, Rebouissou, Sandra, Jeannot, Emmanuelle, Hérault, Aurélie, Saric, Jean, Belghiti, Jacques, Franco, Dominique, Bioulac-Sage, Paulette, Laurent-Puig, Pierre, Zucman-Rossi, Jessica, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Département de Bioinformatique, Ligue Nationale Contre le Cancer (LNCC), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Service de chirurgie digestive, Service de chirurgie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de chirurgie ambulatoire [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), We warmly thank Jacqueline Godet, François Sigaux and Philippe Dessen managers of the Carte d'Identité des Tumeurs (CIT) program founded by the Ligue Nationale contre le Cancer, Daniela Geromin, Christelle Thibault, Patricia Legoix, Damien Gerald, Olivier Bluteau, for their experimental help, Fabien Petel for his help in the submission of the data to EBI, Philippe Bois for critical reading of the manuscript. We thank the technicians from the CEPH, Fondation Jean Dausset for their help in sequencing and all the clinicians that referred the patients. This work was supported by the Ligue Nationale Contre le Cancer and the Fondation de France. SB, SR and EJ are supported by a Fondation de France, a Ligue Nationale Contre le Cancer and a Association pour la Recherche sur le Cancer grant fellowship, respectively., and Zucman-Rossi, Jessica
Subjects: MESH: Mutation, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, ß-catenin, MESH: Cell Cycle Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Liver Neoplasms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], HBV, tumor suppressor gene, MESH: Carcinoma, Hepatocellular, neoplasms, MESH: Genes, Neoplasm, MESH: Adenoma, MESH: Middle Aged, MESH: Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: 1-Phosphatidylinositol 3-Kinase, MESH: Gene Expression Regulation, Neoplastic, digestive system diseases, MESH: Male, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, AKT pathway, MESH: Multigene Family, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microarray, MESH: Female, MESH: Nuclear Pore
Abstract: Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A, and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3CA and TP53. In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1-mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to beta-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and E-cadherin underexpression. CONCLUSION: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies.
Published: 2007
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26. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.: Transcriptome and HCC classification

Author: Boyault, Sandrine, Rickman, David, De Reyniès, Aurélien, Balabaud, Charles, Rebouissou, Sandra, Jeannot, Emmanuelle, Hérault, Aurélie, Saric, Jean, Belghiti, Jacques, Franco, Dominique, Bioulac-Sage, Paulette, Laurent-Puig, Pierre, Zucman-Rossi, Jessica, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Département de Bioinformatique, Ligue Nationale Contre le Cancer, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Service de chirurgie digestive, Service de chirurgie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de chirurgie ambulatoire [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), We warmly thank Jacqueline Godet, François Sigaux and Philippe Dessen managers of the Carte d'Identité des Tumeurs (CIT) program founded by the Ligue Nationale contre le Cancer, Daniela Geromin, Christelle Thibault, Patricia Legoix, Damien Gerald, Olivier Bluteau, for their experimental help, Fabien Petel for his help in the submission of the data to EBI, Philippe Bois for critical reading of the manuscript. We thank the technicians from the CEPH, Fondation Jean Dausset for their help in sequencing and all the clinicians that referred the patients. This work was supported by the Ligue Nationale Contre le Cancer and the Fondation de France. SB, SR and EJ are supported by a Fondation de France, a Ligue Nationale Contre le Cancer and a Association pour la Recherche sur le Cancer grant fellowship, respectively., Genomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), AP-HP - Hôpital Antoine Béclère [Clamart], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)
Subjects: MESH : Carcinoma, Hepatocellular, MESH : Liver Neoplasms, MESH: Mutation, MESH : Gene Expression Regulation, Neoplastic, MESH : Male, MESH : Multigene Family, MESH: DNA, Neoplasm, MESH : Genes, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, ß-catenin, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Cell Cycle Proteins, MESH: Cell Cycle Proteins, MESH: Liver Neoplasms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH : 1-Phosphatidylinositol 3-Kinase, HBV, MESH : Middle Aged, MESH : Female, tumor suppressor gene, MESH: Carcinoma, Hepatocellular, neoplasms, MESH: Genes, Neoplasm, MESH: Adenoma, MESH: Middle Aged, MESH: Humans, MESH : Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: 1-Phosphatidylinositol 3-Kinase, MESH: Gene Expression Regulation, Neoplastic, digestive system diseases, MESH: Male, AKT pathway, MESH : Adenoma, MESH : Nuclear Pore, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Multigene Family, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : DNA, Neoplasm, MESH : Mutation, microarray, MESH: Female, MESH: Nuclear Pore
Abstract: Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A, and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3CA and TP53. In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1-mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to beta-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and E-cadherin underexpression. CONCLUSION: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies.
Published: 2007
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27. Modulation of p53 transcriptional activity by PRIMA-1 and Pifithrin-alpha on staurosporine-induced apoptosis of wild-type and mutated p53 epithelial cells

Author: Jean-Luc Prétet, J. F. Charlot, Christiane Mougin, Magali Nicolier, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
Subjects: Transcription, Genetic, MESH : Hela Cells, Cell, Mutant, Apoptosis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, HeLa, 0302 clinical medicine, MESH: Nerve Tissue Proteins, MESH : Cell Transformation, Viral, Enzyme Inhibitors, MESH: Tumor Suppressor Protein p53, 0303 health sciences, MESH : Cell Line, Transformed, DNA, Neoplasm, Pifithrin, Cell biology, Drug Combinations, MESH : Drug Combinations, MESH: Epithelial Cells, 030220 oncology & carcinogenesis, DNA fragmentation, MESH: Membrane Proteins, MESH : Cell Culture Techniques, MESH: Mitochondria, MESH: Toluene, 03 medical and health sciences, Humans, MESH: Membrane Potentials, MESH: Benzothiazoles, MESH: Drug Combinations, Pharmacology, MESH: Cell Culture Techniques, MESH: Humans, MESH : bcl-2-Associated X Protein, MESH : Humans, Epithelial Cells, Staurosporine, Thiazoles, chemistry, MESH : Membrane Proteins, Mutation, MESH: Female, MESH : Apoptosis, HeLa Cells, Cancer Research, MESH : Staurosporine, Clinical Biochemistry, Cell Culture Techniques, Pharmaceutical Science, MESH : Benzothiazoles, Membrane Potentials, chemistry.chemical_compound, MESH: Papillomaviridae, MESH : Thiazoles, MESH : Membrane Potentials, MESH : Female, Papillomaviridae, MESH : Nerve Tissue Proteins, MESH : Toluene, Cell Line, Transformed, bcl-2-Associated X Protein, Mitochondria, MESH : Epithelial Cells, medicine.anatomical_structure, MESH: Cell Transformation, Viral, MESH: Enzyme Inhibitors, Female, MESH : Mitochondria, MESH : DNA, Neoplasm, MESH : Mutation, medicine.drug, MESH: Mutation, MESH: Cell Line, Tumor, MESH: Thiazoles, MESH: DNA, Neoplasm, Nerve Tissue Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cell Line, Tumor, medicine, MESH: bcl-2-Associated X Protein, Benzothiazoles, MESH: Cell Line, Transformed, MESH : Papillomaviridae, 030304 developmental biology, MESH : Enzyme Inhibitors, MESH : Cell Line, Tumor, MESH: Apoptosis, MESH: Transcription, Genetic, Biochemistry (medical), Wild type, Membrane Proteins, MESH : Transcription, Genetic, Cell Biology, Cell Transformation, Viral, biology.organism_classification, Molecular biology, MESH: Hela Cells, MESH : Tumor Suppressor Protein p53, MESH: Staurosporine, Tumor Suppressor Protein p53, Toluene
Abstract: International audience; We recently argued for a major role of p53 in staurosporine(ST)-induced apoptosis of immortalized epithelial cells, depending on their p53 status. Here, we studied the effects of PRIMA-1 (p53 reactivation and induction of massive apoptosis) and Pifithrin-alpha (p fifty-three inhibitor) in combination with ST to reinforce our previous results by respectively restoring or inhibiting the p53 transcriptional activity in different cell lines.PRIMA-1 does modify neither expression of apoptosis-related proteins nor the percentage of wild-type p53 HeLa and CaSki cells with [symbol: see text]delta psi m and DNA cleavage, whilst it increases by 45% Bax expression and apoptosis of mutated p53 C33A cells. Pifithrin-alpha, does modify neither Bax expression nor apoptosis level of C33A cells, but readily inhibits both [symbol: see text]delta psi m and DNA fragmentation of p53wt cells with decreasing Bax expression. These data support the evidence that PRIMA-1 could be a good candidate, as an anti-cancer drug targeting mutant p53, in order to increase ST efficiency. Moreover, Pifithrin-alpha could be used in combination with ST and PRIMA-1 to prevent side effects of anti-tumor therapies in cells expressing mutant P53.
Published: 2006
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28. Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display

Author: Gitali Ganguli, Christine Wasylyk, Inès Schultz, A. Cromer, Annaïck Carles, Régine Millon, Olivier Poch, F Lemaire, Y. Rabouel, C. Ducray, L. Bracco, C. Zhao, Danièle Muller, Julia Young, P. Marchal, Doulaye Dembélé, Joseph Abecassis, Bohdan Wasylyk, 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), 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 Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I
Subjects: Cancer Research, MESH: Sequence Analysis, DNA, Proteome, Gene Expression, MESH: Amino Acid Sequence, MESH: Base Sequence, Genome, Transcriptome, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Expressed sequence tag, Differential display, Reverse Transcriptase Polymerase Chain Reaction, MESH: Protein Array Analysis, MESH: Genomics, MESH: Carcinoma, Squamous Cell, DNA, Neoplasm, Genomics, Cell cycle, Immunohistochemistry, MESH: Proteome, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, MESH: Computational Biology, MESH: Gene Expression, Molecular Sequence Data, Protein Array Analysis, MESH: DNA, Neoplasm, Computational biology, Biology, 03 medical and health sciences, MESH: Gene Expression Profiling, medicine, Humans, MESH: Blotting, Northern, Amino Acid Sequence, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Cell growth, Gene Expression Profiling, Computational Biology, MESH: Immunohistochemistry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sequence Analysis, DNA, medicine.disease, Blotting, Northern, Head and neck squamous-cell carcinoma, MESH: Head and Neck Neoplasms, MESH: Oligonucleotide Array Sequence Analysis
Abstract: International audience; Head and neck squamous cell carcinoma (HNSCC) is common worldwide and is associated with a poor rate of survival. Identification of new markers and therapeutic targets, and understanding the complex transformation process, will require a comprehensive description of genome expression, that can only be achieved by combining different methodologies. We report here the HNSCC transcriptome that was determined by exhaustive differential display (DD) analysis coupled with validation by different methods on the same patient samples. The resulting 820 nonredundant sequences were analysed by high throughput bioinformatics analysis. Human proteins were identified for 73% (596) of the DD sequences. A large proportion (>50%) of the remaining unassigned sequences match ESTs (expressed sequence tags) from human tumours. For the functionally annotated proteins, there is significant enrichment for relevant biological processes, including cell motility, protein biosynthesis, stress and immune responses, cell death, cell cycle, cell proliferation and/or maintenance and transport. Three of the novel proteins (TMEM16A, PHLDB2 and ARHGAP21) were analysed further to show that they have the potential to be developed as therapeutic targets.
Published: 2006
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29. Primary tumour genetic alterations and intra-tumoral heterogeneity are maintained in xenografts of human colon cancers showing chromosome instability

Author: Erwan Pencreach, Cécile Brigand, Pierre Oudet, Michèle Kedinger, Anne Schneider, M-P Chenard, Isabelle Duluc, Dominique Guenot, Agnès Neuville, M.P. Gaub, Eric Guérin, S Aguillon-Romain, S. du Manoir, 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, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pathology, Colorectal cancer, Loss of Heterozygosity, Allelic Imbalance, Loss of heterozygosity, MESH: Nucleic Acid Hybridization, Mice, 0302 clinical medicine, Nude mouse, Chromosome instability, MESH: Animals, 0303 health sciences, MESH: Genetic Heterogeneity, Nucleic Acid Hybridization, Anatomical pathology, DNA, Neoplasm, 3. Good health, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Colonic Neoplasms, medicine.medical_specialty, Tumour heterogeneity, Transplantation, Heterologous, MESH: DNA, Neoplasm, Mice, Nude, Biology, Pathology and Forensic Medicine, MESH: Chromosomal Instability, 03 medical and health sciences, Genetic Heterogeneity, Chromosomal Instability, medicine, MESH: Mice, Nude, Animals, Humans, Allelotype, MESH: Mice, MESH: Transplantation, Heterologous, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Loss of Heterozygosity, MESH: Humans, MESH: Allelic Imbalance, Chromosome, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, biology.organism_classification, medicine.disease, Disease Models, Animal, MESH: Cell Transformation, Neoplastic, MESH: Disease Models, Animal, MESH: Neoplasm Transplantation, Neoplasm Transplantation
Abstract: International audience; Evaluation of the role of clonal heterogeneity in colon tumour sensitivity/resistance to drugs and/or in conferring metastatic potential requires an adequate experimental model in which the tumour cells maintain the initial genetic alterations and intra-tumoral heterogeneity through maintenance of the genetic clones present in the initial tumour. Therefore, we xenografted subcutaneously into nude mice seven human colonic tumours (from stages B1 to D) that showed chromosome instability and transplanted them sequentially for up to 14 passages. Maintenance after xenografting of the genetic alterations present in the initial tumours was scored by allelotype studies targeting 45 loci localized on 18 chromosomes. We show that xenografting does not alter the genetic or the histological profiles of the tumours even after 14 passages. Screening of the entire genome of one tumour by comparative genome hybridization also showed overall stability of the alterations between the initial and the xenografted tumour. In addition, intra-tumoral heterogeneity was maintained over time, suggesting that no clonal selection occurred in the nude mice. The observation that some loci showed partial allelic imbalance in the initial tumour but loss of heterozygosity after the first passage in nude mice when all the normal cells were lost may allow identification of interesting genetic defects that could be involved in tumour expansion. Thus, sequential xenografts of colon tumours will provide a powerful model for further study of tumour clonality and for the identification of genetic profiles responsible for differential resistance to therapeutic treatments. Our data also suggest that tumour expansion can result from alterations in several distinct genetic pathways.
Published: 2006
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30. Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

Author: Catherine Nguyen, Charles Theillet, Mélanie Nugoli, Lisa Ursule, Carmen Rodríguez, Frédéric Bibeau, Laurence Lasorsa, Nathalie Cervera, Carole Rougé, Paul Chuchana, Béatrice Orsetti, Le Ster, Yves, Génotypes et phénotypes tumoraux, CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'anatomo-pathologie, CRLCC Val d'Aurelle - Paul Lamarque, and This study was supported by funds from INSERM, the Association de Recherche sur le Cancer (ARC), grant 5102, the Ligue Nationale de Lutte Contre le Cancer (LNCC), as part of the « Carte d'Identité des Tumeurs » Program and the joint program « Développement d'outils de diagnostic moléculaire en Cancérologie : Applications aux cancers du sein » Ministère de l'Enseignement Supérieur, de la Recherche et de la Technologie and Fédération Nationale des Centres de Lutte Contre le Cancer. The help of the Génopole Montpellier Languedoc-Roussillon is greatefully acknowledged. M.N. was supported by a doctoral fellowship from the Ligue Nationale Contre le Cancer and C.R. by funds from the Cancéropole Grand Sud Ouest.
Subjects: Cancer Research, Candidate gene, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH: Gene Amplification, MESH: Carcinoma, Lobular, oncogene, Gene duplication, Gene expression, Tumor Cells, Cultured, RNA, Neoplasm, MESH: In Situ Hybridization, Fluorescence, In Situ Hybridization, Fluorescence, Oligonucleotide Array Sequence Analysis, Genetics, Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Ductal, Breast, Nucleic Acid Hybridization, DNA, Neoplasm, Amplicon, Oncology, Chromosomes, Human, Pair 1, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, profiling, MESH: Nuc, DNA, Complementary, MESH: Chromosomes, Human, Pair 1, MESH: DNA, Neoplasm, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Gene Expression Profiling, Gene mapping, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, MESH: Chromosome Aberrations, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, Chromosome Aberrations, MESH: Humans, Gene Expression Profiling, amplicon, Gene Amplification, Chromosome, Genetics and Genomics, MESH: DNA, Complementary, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Gene expression profiling, MESH: Carcinoma, Ductal, Breast, Carcinoma, Lobular, array-CGH, MESH: Female, MESH: Breast Neoplasms
Abstract: International audience; Chromosome 1 is involved in quantitative anomalies in 50-60% of breast tumours. However, the structure of these anomalies and the identity of the affected genes remain to be determined. To characterise these anomalies and define their consequences on gene expression, we undertook a study combining array-CGH analysis and expression profiling using specialised arrays. Array-CGH data showed that 1p was predominantly involved in losses and 1q almost exclusively in gains. Noticeably, high magnitude amplification was infrequent. In an attempt to fine map regions of copy number changes, we defined 19 shortest regions of overlap (SROs) for gains (one at 1p and 18 at 1q) and of 20 SROs for losses (all at 1p). These SROs, whose sizes ranged from 170 kb to 3.2 Mb, represented the smallest genomic intervals possible based on the resolution of our array. The elevated incidence of gains at 1q, added to the well-established concordance between DNA copy increase and augmented RNA expression, made us focus on gene expression changes at this chromosomal arm. To identify candidate oncogenes, we studied the RNA expression profiles of 307 genes located at 1q using a home-made built cDNA array. We identified 30 candidate genes showing significant overexpression correlated to copy number increase. In order to substantiate their involvement, RNA expression levels of these candidate genes were measured by quantitative (Q)-RT-PCR in a panel of 25 breast cancer cell lines previously typed by array-CGH. Q-PCR showed that 11 genes were significantly overexpressed in the presence of a genomic gain in these cell lines, and 20 overexpressed when compared to normal breast.
Published: 2006
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31. Feature extraction and signal processing for nylon DNA microarrays

Author: François Bertucci, Béatrice Loriod, Samuel Granjeaud, Rémi Houlgatte, Fabrice Lopez, Jacques Rougemont, Aude Bourgeois, Laurence Loï, Pascal Hingamp, Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'oncogénétique moléculaire, Université de la Méditerranée - Aix-Marseille 2, Part of this research was supported by the Temblor project EU grant QLRT-2001-00015, by the CIT program of the Ligue Nationale Contre le Cancer and by Marseille-Genopole., Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Maylin, Françoise
Subjects: Algorithms, Animals, Arabidopsis Proteins, Bias (Epidemiology), Breast Neoplasms, Carbon-Oxygen Ligases, Cluster Analysis, DNA, Neoplasm, DNA, Plant, Densitometry, Discriminant Analysis, Gene Expression Profiling, Humans, Image Processing, Computer-Assisted, Mice, Nylons, Oligonucleotide Array Sequence Analysis, Phosphorus Radioisotopes, Polymerase Chain Reaction, RNA, Messenger, Reproducibility of Results, Signal Processing, Computer-Assisted, Software, MESH: Densitometry, 0302 clinical medicine, MESH: Carbon-Oxygen Ligases, Potential source, MESH: Animals, Genetics, 0303 health sciences, Signal processing, Methodology Article, MESH: Comparative Study, MESH: Bias (Epidemiology), 3. Good health, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], DNA microarray, Biological system, Biotechnology, lcsh:QH426-470, lcsh:Biotechnology, Feature extraction, MESH: DNA, Neoplasm, MESH: Algorithms, MESH: Arabidopsis Proteins, Biology, MESH: Image Processi, 03 medical and health sciences, MESH: Gene Expression Profiling, Bias, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:TP248.13-248.65, Cluster analysis, MESH: DNA, Plant, 030304 developmental biology, MESH: Humans, business.industry, MESH: Discriminant Analysis, Linear discriminant analysis, MESH: Cluster Analysis, Gene expression profiling, lcsh:Genetics, business, MESH: Breast Neoplasms
Abstract: Background High-density DNA microarrays require automatic feature extraction methodologies and softwares. These can be a potential source of non-reproducibility of gene expression measurements. Variation in feature location or in signal integration methodology may be a significant contribution to the observed variance in gene expression levels. Results We explore sources of variability in feature extraction from DNA microarrays on Nylon membrane with radioactive detection. We introduce a mathematical model of the signal emission and derive methods for correcting biases such as overshining, saturation or variation in probe amount. We also provide a quality metric which can be used qualitatively to flag weak or untrusted signals or quantitatively to modulate the weight of each experiment or gene in higher level analyses (clustering or discriminant analysis). Conclusions Our novel feature extraction methodology, based on a mathematical model of the radioactive emission, reduces variability due to saturation, neighbourhood effects and variable probe amount. Furthermore, we provide a fully automatic feature extraction software, BZScan, which implements the algorithms described in this paper.
Published: 2004
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32. Cure of Fisher rats bearing radioresistant F98 glioma treated with cis-platinum and irradiated with monochromatic synchrotron X-rays

Author: Marie-Claude Biston, Aurélie Joubert, François Estève, Hélène Elleaume, Anne-Marie Charvet, Jean-François Adam, Jacques Balosso, Sylvain Bohic, Nicolas Foray, Rayonnement Synchrotron et Recherche Medicale (RSRM), Université Joseph Fourier - Grenoble 1 (UJF)-European Synchrotron Radiation Facility (ESRF)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Synchrotron Radiation Facility (ESRF), Service d'Imagerie par Résonance Magnétique (IRM), CHU Grenoble, Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon, Serduc, Raphael, and European Synchrotron Radiation Facility (ESRF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Cancer Research, MESH: Combined Modality Therapy, DNA Repair, MESH: Rats, medicine.medical_treatment, Synchrotron radiation, MESH: DNA, Neoplasm, Antineoplastic Agents, Radiation Tolerance, MESH: Glioma, MESH: X-Rays, In vivo, Radioresistance, Glioma, medicine, Animals, MESH: Animals, Irradiation, neoplasms, MESH: DNA Damage, MESH: DNA Repair, Chemotherapy, MESH: Radiation Tolerance, Brain Neoplasms, Chemistry, business.industry, MESH: Rats, Inbred F344, X-Rays, X-ray, Cancer, DNA, Neoplasm, equipment and supplies, medicine.disease, Combined Modality Therapy, Rats, Inbred F344, MESH: Male, Rats, Oncology, MESH: Cisplatin, MESH: Brain Neoplasms, MESH: Synchrotrons, MESH: Antineoplastic Agents, Cisplatin, Nuclear medicine, business, Synchrotrons, DNA Damage
Abstract: High-grade gliomas are usually of poor prognosis, and conventional radiotherapy, even combined with chemotherapy, still fails to improve the survival of patients. Here, we propose an innovative therapeutic approach combining synchrotron radiation with cis-diamminedichloroplatinum (II) (CDDP). As suggested previously, monochromatic synchrotron irradiation of CDDP at 78.8 keV, just above the 78.4 keV platinum absorption K-edge, leads to an enhanced photoelectric effect and an increased local toxicity. To select a particular radiation energy that could provide supra-additive effect, we used pulsed-field gel electrophoresis to assess yields of DNA double-strand breaks induced in rat F98 glioma cells after CDDP treatment combined with synchrotron X-rays. Thereafter, intracerebral CDDP injection combined with synchrotron X-rays was applied to Fisher rats bearing F98 glioma. CDDP concentrations were mapped by synchrotron X-ray microfluorescence. An extra number of more slowly repaired double strand breaks were observed when irradiating CDDP-treated F98 cells at 78.8 keV. In vivo treatments were then performed with different radiation doses and CDDP concentrations. All cell inoculations in rat brain resulted in tumor development, and tumor presence was controlled by computed tomography. Among all of the conditions tested, the combination of 3 μg of CDDP with 15 Gy resulted in the largest median survival time (206 days). After 1 year, about 34% of treated rats were still alive. This preclinical finding, validated by molecular analysis, represents the most protracted survival reported with this radioresistant glioma model and demonstrates the interest in powerful monochromatic X-ray sources as new tools for cancer treatments.
Published: 2004

33. In vivo evolution of tumour cells after the generation of double-strand DNA breaks

Author: Lluis M. Mir, F. Z. El Kebir, A Spatz, O Tounekti, M Cemazar, H. Mekid, Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie et Technobiologie, Faculté des Sciences Mathématiques, Physiques et Naturelles de Tunis (FST), Université de Tunis El Manar (UTM)-Université de Tunis El Manar (UTM), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Institute of Oncology - Ljubljana, Institute of Oncology Ljubljana, Laboratoire de Biologie du Développement, and University of Oran Es-Senia [Oran] | Université d'Oran Es-Senia [Oran]
Subjects: Cancer Research, Pathology, DNA Repair, Cell division, Melanoma, Experimental, Apoptosis, MESH: Sarcoma, Experimental, Immunoenzyme Techniques, in vivo electropermeabilization, Mice, 0302 clinical medicine, MESH: Caspase 3, Tumor Cells, Cultured, MESH: Animals, MESH: In Situ Nick-End Labeling, MESH: DNA Repair, 0303 health sciences, Caspase 3, MESH: DNA, MESH: Electric Stimulation, DNA, Neoplasm, MESH: Bleomycin, mitotic cell death, MESH: Melanoma, Experimental, Oncology, Caspases, 030220 oncology & carcinogenesis, Pseudoapoptosis, Sarcoma, Experimental, electroporation, medicine.medical_specialty, Programmed cell death, MESH: Mutation, DNA repair, DNA damage, Mitosis, MESH: DNA, Neoplasm, MESH: Microscopy, Electron, Biology, Bleomycin, 03 medical and health sciences, MESH: Mice, Inbred C57BL, In Situ Nick-End Labeling, medicine, Animals, Experimental Therapeutics, MESH: Tumor Cells, Cultured, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Immunoenzyme Techniques, MESH: Mice, 030304 developmental biology, MESH: DNA Damage, MESH: Caspases, MESH: Apoptosis, DNA, MESH: Mitosis, Electric Stimulation, Mice, Inbred C57BL, Microscopy, Electron, electrochemotherapy, Mutation, Cancer cell, Cancer research, DNA Damage
Abstract: In vitro, the ratio of single- to double-strand DNA breaks (DSB) and their absolute values determine the cell death pathway. The consequences of the generation of various numbers of DSB generated in vivo in tumour cells have been analysed in two different experimental tumour models. Synchronisation of DSB generation and control of their number have been achieved using different doses of bleomycin (BLM) and tumour cell permeabilisation by means of locally delivered electric pulses. According to BLM dose, different cell death pathways are observed. At a low therapeutic dose, a mitotic cell death pathway is detected. It is characterised by the appearance of 'atypical mitosis', TUNEL and caspase-3 positive, 24 h after the treatment, and later by the presence of typical apoptotic figures, mainly TUNEL positive but caspase-3 negative. Caspase-3 is thus an early marker of apoptosis. Mitotic cell death is also followed by lymphocytic infiltration reaction. At high doses of BLM, pseudoapoptosis is detected within a few minutes after the treatment. These cell death pathways are discussed as a function of the number of DSB generated, by comparison with previous results obtained in vitro using BLM or ionising radiation.
Published: 2003
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34. Cytostatic effect of polyethylene glycol on human colonic adenocarcinoma cells

Author: Laurence Gamet-Payrastre, Géraldine Parnaud, Denis E. Corpet, ProdInra, Migration, Xénobiotiques, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Cancer Research, MESH: Flow Cytometry, Apoptosis, Sodium Chloride, Polyethylene Glycols, chemistry.chemical_compound, MESH: Osmolar Concentration, Tumor Cells, Cultured, Sorbitol, Osmotic pressure, MESH: Cell Size, colorectal, intestinal, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, cancer prevention, cytostatique, MESH: G0 Phase, Cell Differentiation, DNA, Neoplasm, Flow Cytometry, CANCER, HT29, 3. Good health, Oncology, Biochemistry, CaCo2, polyethylene glycol, Colonic Neoplasms, MESH: Cell Division, MESH: Caco-2 Cells, Cell Division, MESH: Cell Differentiation, MESH: Cell Nucleus, MESH: Sodium Chloride, PRESSION OSMOTIQUE, mechanism, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, macromolecular substances, Polyethylene glycol, Adenocarcinoma, Biology, MESH: G1 Phase, Resting Phase, Cell Cycle, Osmotic Pressure, anit-cancer, PEG ratio, Humans, AGENT CHEMOPREVENTIF, MESH: Tumor Cells, Cultured, Lactic Acid, Cell Size, MESH: Colonic Neoplasms, Cell Nucleus, MESH: Humans, colon, Osmotic concentration, Cell growth, MESH: Apoptosis, MESH: Adenocarcinoma, Cell Membrane, Osmolar Concentration, G1 Phase, technology, industry, and agriculture, MESH: Osmotic Pressure, PEG, Molecular biology, Culture Media, rats, MESH: Polyethylene Glycols, chemistry, Caco-2, Cell culture, Cancer cell, MESH: Culture Media, cells, MESH: Antineoplastic Agents, MESH: Lactic Acid, MESH: Sorbitol, Caco-2 Cells, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Cell Membrane
Abstract: International audience; Polyethylene glycol (PEG 8000) is a potent cancer chemopreventive agent. This osmotic laxative polymer markedly suppresses colon cancer in rats. To explain the mechanism, we have tested the in vitro effect of PEG on four human cell lines. Two poorly differentiated adenocarcinoma lines (HT29 and COLO205), a fetal mucosa line (FHC) and a differentiated line (post-confluent Caco-2) were incubated with various PEG concentrations for 2-5 days. Results show that PEG markedly and dose-dependently inhibited HT29 and COLO205 cell growth. This cytostatic effect was associated with a blocking of the cell cycle in G0/G1 phase. In addition, PEG decreased the viability of HT29 and COLO205 adenocarcinoma cells. In contrast, post-confluent intestinal-like Caco-2 cells and normal FHC cells were, respectively, not or little affected by PEG. Moreover, the lactate concentration increased twofold in the medium of PEG-treated HT29 cells compared with untreated cells. Microscopic observations showed that PEG induced cell shrinking, membrane blebbing and the condensation of nuclear chromatin. However, because no DNA ladder and no annexin staining were detected, we presume that PEG did not induce apoptosis. PEG increased the osmotic pressure of the culture medium. Hyperosmotic media with added NaCl or sorbitol also inhibited HT29 cell growth, and increased lactate release. These results suggest that PEG may be selectively cytostatic for proliferating cancer cells. This growth inhibition may be due to the high osmotic pressure induced by PEG in vitro. Because the osmotic pressure is high in feces of PEG-fed rats, it may explain the suppression of colon carcinogenesis by PEG.
Published: 2001

35. Comprehensive allelotyping of human hepatocellular carcinoma

Author: Hisaki Nagai, Anne Dejean, Pascal Pineau, Marie Annick Buendia, Pierre Tiollais, Cheriet Rauline, Samia, Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported in part by grants from the Ligue Nationale contre le Cancer and the Association pour la Recherche sur le Cancer. HN was supported by a grant from the Ligue Nationale contre le Cancer. PP was supported by grants from the Fondation pour la Recherche Médicale and the Institut Electricité-Santé., and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cancer Research, [SDV]Life Sciences [q-bio], Polymerase Chain Reaction, Loss of heterozygosity, 0302 clinical medicine, MESH: Liver Neoplasms, Chromosomes, Human, hepatitis, tumor suppressor gene, MESH: Carcinoma, Hepatocellular, MESH: Heterozygote, Genetics, 0303 health sciences, Liver cell, Liver Neoplasms, hepatocellular carcinoma, DNA, Neoplasm, MESH: DNA, Satellite, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Hepatocellular carcinoma, loss of heterozygosity, Liver cancer, Heterozygote, Carcinoma, Hepatocellular, Tumor suppressor gene, MESH: DNA, Neoplasm, Locus (genetics), Biology, DNA, Satellite, MESH: Chromosomes, Human, 03 medical and health sciences, Gene mapping, MESH: Polymorphism, Genetic, Carcinoma, medicine, Humans, Molecular Biology, neoplasms, MESH: Genome, Human, Alleles, 030304 developmental biology, MESH: Humans, Polymorphism, Genetic, Genome, Human, MESH: Alleles, MESH: Polymerase Chain Reaction, microsatellite markers, medicine.disease, digestive system diseases, MESH: Gene Deletion, Cancer research, Gene Deletion
Abstract: International audience; Hepatocellular carcinoma (HCC) is one of the most common cancers in many parts of the world, however the molecular mechanisms underlying liver cell transformation remain obscure. A genome-wide scan of loss of heterozygosity (LOH) in tumors provides a powerful tool to search for genes involved in neoplastic processes. To identify recurrent genetic alterations in liver tumors, we examined DNAs isolated from 120 HCCs and their adjacent non tumorous parts for LOH using a collection of 195 microsatellite markers located roughly every 20 cM throughout 39 autosomal arms. The mean heterozygosity was 73%. Our findings provide additional support that LOH for loci on chromosomal arms 1p, 4q, 6q, 8p, 13q and 16p is significantly elevated in HCC. The highest percentage of LOH is found for a locus in 8p23 (42% of informative csaes). This corresponds to one of the most common genetic abnormalities reported to date in these tumors. In addition, high ratio of LOH (> or = 35%) is observed on chromosome arms which had not been implicated in previous studies, notably on 1q, 2q and 9q. No correlation was found between LOH of specific chromosomal regions and etiologic factors such as chronic infections with hepatitis B or C viruses. This first report of an extensive allelotypic analysis of HCC should help in identifying new genes whose loss of function contributes to the development of liver cancer.
Published: 1997
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36. Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization

Author: Pascal Pineau, Anne Dejean, Agnès Marchio, Pierre Tiollais, Gisèle Danglot, Alain Bernheim, Mounira Meddeb, Recombinaison et Expression Génétique, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Cytogénetique et Génétique Oncologiques [Villejuif], Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the Ligue Nationale Française contre le Cancer and the Association pour la Recherche contre le Cancer. P.P. was supported by grants from the Fondation pour la Recherche Médicale and the Institut Electricité-Santé., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cancer Research, Carcinoma, Hepatocellular, [SDV]Life Sciences [q-bio], MESH: DNA, Neoplasm, Chromosome Disorders, Biology, medicine.disease_cause, MESH: Gene Amplification, Pathogenesis, MESH: Nucleic Acid Hybridization, MESH: Liver Neoplasms, Chromosome regions, Genetics, medicine, Tumor Cells, Cultured, Humans, MESH: Chromosome Aberrations, MESH: Tumor Cells, Cultured, MESH: Carcinoma, Hepatocellular, MESH: Metaphase, Molecular Biology, Metaphase, Hepatitis B virus, Chromosome Aberrations, MESH: Chromosome Disorders, MESH: Humans, Hepatology, MESH: Hepatitis B, MESH: Chronic Disease, Liver Neoplasms, Gene Amplification, Cancer, Nucleic Acid Hybridization, DNA, Neoplasm, HCCS, medicine.disease, Hepatitis B, Molecular biology, 3. Good health, Infectious Diseases, Hepatocellular carcinoma, Chronic Disease, Liver cancer, Comparative genomic hybridization
Abstract: Comparative genomic hybridization (CGH) was used to evaluate and map genomic aberrations in 50 hepatocellular carcinomas (HCCs) from patients chronically infected with hepatitis B virus (HBV). CGH clearly detected nonrandom genomic imbalances. Losses were most prevalent on chromosome regions 4q (70%), 8p (65%), 16q (54%), 17p (51%), 13q and 6q (37% each), and 1p (30%). The most frequent gains occurred on 8q (60%), 1q (58%), and 6p and 17q (33% each). In a few cases, sequence amplifications were detected that were mapped to bands 11q12, 12p11, 14q12, and 19q13.1. This study represents the first analysis of primary liver cancers by CGH, and it confirms the presence of previously known chromosomal aberrations in HCC and highlights new quantitative abnormalities and sequence amplifications. These findings should lead to the characterization of new loci involved in liver cancer pathogenesis. Genes Chromosom. Cancer 18:59–65, 1997. © 1997 Wiley-Liss, Inc.
Published: 1997
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37. Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma

Author: A, Dejean, H, de Thé, Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Hepatitis B virus, Carcinoma, Hepatocellular, MESH: Mutation, Genes, Viral, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Molecular Sequence Data, MESH: DNA, Neoplasm, Tretinoin, MESH: Carrier Proteins, MESH: Amino Acid Sequence, MESH: Base Sequence, MESH: Liver Neoplasms, Humans, Amino Acid Sequence, MESH: Carcinoma, Hepatocellular, MESH: Organ Specificity, Recombination, Genetic, MESH: Receptors, Retinoic Acid, MESH: Genes, Viral, MESH: Humans, MESH: Molecular Sequence Data, MESH: Tretinoin, Base Sequence, MESH: Hepatitis B, Liver Neoplasms, MESH: DNA, DNA, DNA, Neoplasm, Exons, MESH: Gene Expression Regulation, Neoplastic, Hepatitis B, digestive system diseases, MESH: DNA, Viral, Gene Expression Regulation, Neoplastic, MESH: Hepatitis B virus, Cell Transformation, Neoplastic, Organ Specificity, MESH: Cell Transformation, Neoplastic, DNA, Viral, Mutation, MESH: Recombination, Genetic, Carrier Proteins, MESH: Exons
Abstract: International audience; Chronic hepatitis B virus (HBV) infection is etiologically related to human hepatocellular carcinoma (HCC). Most HCCs contain integrated HBV DNA in the liver cellular DNA, suggesting that the integration may be involved in carcinogenesis. From a comparison of a single HBV integration site present in a hepatoma with the corresponding unoccupied site in the non-tumourous tissue of the same liver, we have shown that HBV DNA inserted in a putative cellular exon with striking similarity to the DNA-binding domain of the thyroid/steroid hormone receptors. The corresponding cDNA has been isolated (hap gene) and shown to encode the retinoic acid receptor. In the original patient, integration took place so that the first codons of the viral surface protein gene became fused in frame with most of the hap gene. Because retinoic acid is known to regulate the transcription of target genes crucial for cellular growth and differentiation, it is most probable that consequent to the HBV insertion, hap, usually transcribed at a very low level in normal hepatocytes, became inappropriately expressed as an altered chimaeric retinoic acid receptor, thus contributing to the cell transformation. These results strongly support the possibility that HBV may play a direct role in liver carcinogenesis by insertional mutagenesis.
Published: 1990

38. Organization and expression of hepatitis B sequences cloned from hepatocellular carcinoma tissue DNA

Author: Dejean, Anne, Carloni, Guido, Bréchot, Christian, Tiollais, Pierre, Wain-Hobson, Simon, Recombinaison et expression génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Applications du génie génétique (G3), Institut Pasteur [Paris] (IP), This work was supported by INSERM grants ATP 72.79/104 and 124036 and grants from the Ministère de la Recherche et de la Technologie., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], and Cheriet Rauline, Samia
Subjects: Carcinoma, Hepatocellular, Genes, Viral, [SDV]Life Sciences [q-bio], gene cloning, MESH: DNA, Neoplasm, MESH: Base Sequence, MESH: Liver Neoplasms, integrated DNA, Humans, MESH: Cloning, Molecular, Cloning, Molecular, MESH: Carcinoma, Hepatocellular, MESH: Genes, Viral, Hepatitis B Surface Antigens, MESH: Humans, Base Sequence, Liver Neoplasms, DNA, Neoplasm, hepatocellular carcinoma, Cell Transformation, Viral, MESH: Gene Expression Regulation, tk cotransformation, MESH: Hepatitis B Surface Antigens, [SDV] Life Sciences [q-bio], MESH: Hepatitis B virus, Gene Expression Regulation, MESH: Cell Transformation, Viral, hepatitis B virus, HBsAg expression
Abstract: International audience; We have constructed a phage lambda library of liver DNA fragments from West African patient who died of liver failure due to advanced hepatocellular carcinoma. Four hepatitis B virus (HBV) DNA-carrying recombinants have been isolated, one clone (lambda IA22) being analyzed in greatest detail. It contains approximately 3.8 kb of HBV DNA without detectable deletions or rearrangements. One site of integration lies close to the nick in free viral DNA. The restriction map of the HBV sequences is close to those published for the ay subtype. Coconvection of mouse Ltk- cells with lambda IA22 and cloned thymidine kinase gene results in the expression of gene S and the excretion of hepatitis B surface antigen (HBsAg) particles into the culture supernatant.
Published: 1982
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39. Specific hepatitis B virus integration in hepatocellular carcinoma DNA through a viral 11-base-pair direct repeat

Author: Pierre Tiollais, Anne Dejean, Pierre Sonigo, Simon Wain-Hobson, Recombinaison et expression génétique, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported in part by the Université Paris VII, la Ligue Nationale contre le Cancer, and l'Ecole Normale Supérieure., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Cheriet Rauline, Samia
Subjects: Hepatitis B virus, Carcinoma, Hepatocellular, Base pair, [SDV]Life Sciences [q-bio], MESH: DNA, Neoplasm, MESH: DNA Restriction Enzymes, Biology, MESH: Base Sequence, medicine.disease_cause, DNA sequencing, MESH: Nucleic Acid Hybridization, 03 medical and health sciences, chemistry.chemical_compound, Nucleic acid thermodynamics, 0302 clinical medicine, Restriction map, MESH: Base Composition, MESH: Liver Neoplasms, medicine, Humans, MESH: Cloning, Molecular, Cloning, Molecular, MESH: Carcinoma, Hepatocellular, 030304 developmental biology, Genetics, 0303 health sciences, Base Composition, Multidisciplinary, MESH: Humans, Base Sequence, Liver Neoplasms, Nucleic Acid Hybridization, DNA Restriction Enzymes, DNA, Neoplasm, Virology, 3. Good health, MESH: DNA, Viral, [SDV] Life Sciences [q-bio], MESH: Hepatitis B virus, chemistry, DNA, Viral, 030211 gastroenterology & hepatology, Human genome, DNA, In vitro recombination, Research Article
Abstract: International audience; Integrated hepatitis B virus (HBV) DNA sequences have been cloned from cellular DNA of two human liver tumors. The structure of the clones was determined by restriction mapping, and the host-viral DNA junctions were sequenced. In each clone one junction mapped to within an 11-base-pair sequence, 5' T-T-C-A-C-C-T-C-T-G-C, which is directly repeated near the extremities of the cohesive-end region of the free viral genome. The two copies of this sequence are termed DR1 and DR2. While one clone carried a host-viral junction within DR1, the second one carried a host-viral junction within DR2. The first 1 or 2 base pairs of the repeat were deleted upon recombination with the host genome, leaving at the junctions a common 9-base-pair segment of HBV DNA, 5' C-A-C-C-T-C-T-G-C. The other two host-viral junctions mapped to the pre-S region and to the core region of the viral genome, showing no peculiar feature. These results show that HBV DNA can integrate via a specific viral DNA sequence.
Published: 1984
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40. The cloned human oestrogen receptor contains a mutation which alters its hormone binding properties

Author: Daniel Metzger, Mathurose Ponglikitmongkol, Laszlo Tora, I. Park, A. Mullick, Pierre Chambon, Laboratoire de Génetique Moléculaire des Eucaryotes (LGME), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Oligonucleotide Probes, [SDV]Life Sciences [q-bio], DNA-Directed DNA Polymerase, MESH: Base Sequence, medicine.disease_cause, MESH: Gene Amplification, MESH: Valine, 0302 clinical medicine, MESH: DNA-Directed DNA Polymerase, Cloning, Molecular, Receptor, chemistry.chemical_classification, 0303 health sciences, Mutation, MESH: Kinetics, General Neuroscience, Valine, DNA, Neoplasm, MESH: Genes, MESH: Glycine, Amino acid, Receptors, Estrogen, Biochemistry, 030220 oncology & carcinogenesis, MESH: Receptors, Estrogen, Female, Research Article, Binding domain, MESH: Mutation, Molecular Sequence Data, Glycine, MESH: DNA, Neoplasm, Breast Neoplasms, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Complementary DNA, medicine, Humans, MESH: Cloning, Molecular, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, General Immunology and Microbiology, Point mutation, Gene Amplification, Molecular biology, MESH: Cell Line, Kinetics, Genes, chemistry, Oligonucleotide Probes, MESH: Female, MESH: Breast Neoplasms
Abstract: International audience; We demonstrate here that the human oestrogen receptor (hER) cDNA clone pOR8 obtained from MCF-7 cells contains an artefactual point mutation which results in the substitution of a valine for a glycine at amino acid position 400 (Gly-400----Val-400). This mutation in the hormone binding domain of the cloned hER destabilizes its structure and decreases its apparent affinity for oestradiol at 25 degrees C, but not at 4 degrees C, when compared with the wild-type hER with a Gly-400.

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