Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma
Identifieur interne : 000570 ( Pmc/Curation ); précédent : 000569; suivant : 000571Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma
Auteurs : Anneleen Decock [Belgique] ; Maté Ongenaert [Belgique] ; Robrecht Cannoodt [Belgique] ; Kimberly Verniers [Belgique] ; Bram De Wilde [Belgique] ; Geneviève Laureys [Belgique] ; Nadine Van Roy [Belgique] ; Ana P. Berbegall [Espagne] ; Julie Bienertova-Vasku [République tchèque] ; Nick Bown [Royaume-Uni] ; Nathalie Clément [France] ; Valérie Combaret [France] ; Michelle Haber [Australie] ; Claire Hoyoux [Belgique] ; Jayne Murray [Australie] ; Rosa Noguera [Espagne] ; Gaelle Pierron [France] ; Gudrun Schleiermacher [France] ; Johannes H. Schulte [Allemagne] ; Ray L. Stallings [Irlande (pays)] ; Deborah A. Tweddle [Royaume-Uni] ; Katleen De Preter [Belgique] ; Frank Speleman [Belgique] ; Jo Vandesompele [Belgique]Source :
- Oncotarget [ 1949-2553 ] ; 2015.
Abstract
Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in
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PubMed: 26646589
PubMed Central: 4811509
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wicri:level="1"><nlm:aff id="A6"> Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Van Roy, Nadine" sort="Van Roy, Nadine" uniqKey="Van Roy N" first="Nadine" last="Van Roy">Nadine Van Roy</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Berbegall, Ana P" sort="Berbegall, Ana P" uniqKey="Berbegall A" first="Ana P." last="Berbegall">Ana P. 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Brno</wicri:regionArea></affiliation></author><author><name sortKey="Bown, Nick" sort="Bown, Nick" uniqKey="Bown N" first="Nick" last="Bown">Nick Bown</name><affiliation wicri:level="1"><nlm:aff id="A9"> Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne</wicri:regionArea></affiliation></author><author><name sortKey="Clement, Nathalie" sort="Clement, Nathalie" uniqKey="Clement N" first="Nathalie" last="Clément">Nathalie Clément</name><affiliation wicri:level="1"><nlm:aff id="A10"> Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Combaret, Valerie" sort="Combaret, Valerie" uniqKey="Combaret V" first="Valérie" last="Combaret">Valérie Combaret</name><affiliation wicri:level="1"><nlm:aff id="A11"> Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon</wicri:regionArea></affiliation></author><author><name sortKey="Haber, Michelle" sort="Haber, Michelle" uniqKey="Haber M" first="Michelle" last="Haber">Michelle Haber</name><affiliation wicri:level="1"><nlm:aff id="A12"> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW</wicri:regionArea></affiliation></author><author><name sortKey="Hoyoux, Claire" sort="Hoyoux, Claire" uniqKey="Hoyoux C" first="Claire" last="Hoyoux">Claire Hoyoux</name><affiliation wicri:level="1"><nlm:aff id="A13"> Pediatric Hemato-oncology, CHR Citadelle, Liège, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Pediatric Hemato-oncology, CHR Citadelle, Liège</wicri:regionArea></affiliation></author><author><name sortKey="Murray, Jayne" sort="Murray, Jayne" uniqKey="Murray J" first="Jayne" last="Murray">Jayne Murray</name><affiliation wicri:level="1"><nlm:aff id="A12"> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW</wicri:regionArea></affiliation></author><author><name sortKey="Noguera, Rosa" sort="Noguera, Rosa" uniqKey="Noguera R" first="Rosa" last="Noguera">Rosa Noguera</name><affiliation wicri:level="1"><nlm:aff id="A7"> Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea> Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia</wicri:regionArea></affiliation></author><author><name sortKey="Pierron, Gaelle" sort="Pierron, Gaelle" uniqKey="Pierron G" first="Gaelle" last="Pierron">Gaelle Pierron</name><affiliation wicri:level="1"><nlm:aff id="A14"> Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Schleiermacher, Gudrun" sort="Schleiermacher, Gudrun" uniqKey="Schleiermacher G" first="Gudrun" last="Schleiermacher">Gudrun Schleiermacher</name><affiliation wicri:level="1"><nlm:aff id="A15"> U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Schulte, Johannes H" sort="Schulte, Johannes H" uniqKey="Schulte J" first="Johannes H." last="Schulte">Johannes H. Schulte</name><affiliation wicri:level="1"><nlm:aff id="A16"> Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, HufelandstraΔe, Essen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea> Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, HufelandstraΔe, Essen</wicri:regionArea></affiliation></author><author><name sortKey="Stallings, Ray L" sort="Stallings, Ray L" uniqKey="Stallings R" first="Ray L." last="Stallings">Ray L. Stallings</name><affiliation wicri:level="1"><nlm:aff id="A17"> National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea> National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A18"> Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, York House, Dublin, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea> Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, York House, Dublin</wicri:regionArea></affiliation></author><author><name sortKey="Tweddle, Deborah A" sort="Tweddle, Deborah A" uniqKey="Tweddle D" first="Deborah A." last="Tweddle">Deborah A. Tweddle</name><affiliation wicri:level="1"><nlm:aff id="A19"> Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne</wicri:regionArea></affiliation></author><author><name sortKey="De Preter, Katleen" sort="De Preter, Katleen" uniqKey="De Preter K" first="Katleen" last="De Preter">Katleen De Preter</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A3"> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Speleman, Frank" sort="Speleman, Frank" uniqKey="Speleman F" first="Frank" last="Speleman">Frank Speleman</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Vandesompele, Jo" sort="Vandesompele, Jo" uniqKey="Vandesompele J" first="Jo" last="Vandesompele">Jo Vandesompele</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A3"> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26646589</idno><idno type="pmc">4811509</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811509</idno><idno type="RBID">PMC:4811509</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000570</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000570</idno><idno type="wicri:Area/Pmc/Curation">000570</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000570</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma</title><author><name sortKey="Decock, Anneleen" sort="Decock, Anneleen" uniqKey="Decock A" first="Anneleen" last="Decock">Anneleen Decock</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Ongenaert, Mate" sort="Ongenaert, Mate" uniqKey="Ongenaert M" first="Maté" last="Ongenaert">Maté Ongenaert</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Cannoodt, Robrecht" sort="Cannoodt, Robrecht" uniqKey="Cannoodt R" first="Robrecht" last="Cannoodt">Robrecht Cannoodt</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A3"> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A4"> DAMBI, VIB Inflammation Research Center, Technologiepark, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> DAMBI, VIB Inflammation Research Center, Technologiepark, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5"> Department of Respiratory Medicine, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Department of Respiratory Medicine, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Verniers, Kimberly" sort="Verniers, Kimberly" uniqKey="Verniers K" first="Kimberly" last="Verniers">Kimberly Verniers</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="De Wilde, Bram" sort="De Wilde, Bram" uniqKey="De Wilde B" first="Bram" last="De Wilde">Bram De Wilde</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A6"> Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Laureys, Genevieve" sort="Laureys, Genevieve" uniqKey="Laureys G" first="Geneviève" last="Laureys">Geneviève Laureys</name><affiliation wicri:level="1"><nlm:aff id="A6"> Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Van Roy, Nadine" sort="Van Roy, Nadine" uniqKey="Van Roy N" first="Nadine" last="Van Roy">Nadine Van Roy</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Berbegall, Ana P" sort="Berbegall, Ana P" uniqKey="Berbegall A" first="Ana P." last="Berbegall">Ana P. Berbegall</name><affiliation wicri:level="1"><nlm:aff id="A7"> Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea> Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia</wicri:regionArea></affiliation></author><author><name sortKey="Bienertova Vasku, Julie" sort="Bienertova Vasku, Julie" uniqKey="Bienertova Vasku J" first="Julie" last="Bienertova-Vasku">Julie Bienertova-Vasku</name><affiliation wicri:level="1"><nlm:aff id="A8"> Department of Pathological Physiology, Department of Pediatric Oncology, Masaryk University, Černopolní, Brno, Czech Republic</nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea> Department of Pathological Physiology, Department of Pediatric Oncology, Masaryk University, Černopolní, Brno</wicri:regionArea></affiliation></author><author><name sortKey="Bown, Nick" sort="Bown, Nick" uniqKey="Bown N" first="Nick" last="Bown">Nick Bown</name><affiliation wicri:level="1"><nlm:aff id="A9"> Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne</wicri:regionArea></affiliation></author><author><name sortKey="Clement, Nathalie" sort="Clement, Nathalie" uniqKey="Clement N" first="Nathalie" last="Clément">Nathalie Clément</name><affiliation wicri:level="1"><nlm:aff id="A10"> Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Combaret, Valerie" sort="Combaret, Valerie" uniqKey="Combaret V" first="Valérie" last="Combaret">Valérie Combaret</name><affiliation wicri:level="1"><nlm:aff id="A11"> Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon</wicri:regionArea></affiliation></author><author><name sortKey="Haber, Michelle" sort="Haber, Michelle" uniqKey="Haber M" first="Michelle" last="Haber">Michelle Haber</name><affiliation wicri:level="1"><nlm:aff id="A12"> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW</wicri:regionArea></affiliation></author><author><name sortKey="Hoyoux, Claire" sort="Hoyoux, Claire" uniqKey="Hoyoux C" first="Claire" last="Hoyoux">Claire Hoyoux</name><affiliation wicri:level="1"><nlm:aff id="A13"> Pediatric Hemato-oncology, CHR Citadelle, Liège, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Pediatric Hemato-oncology, CHR Citadelle, Liège</wicri:regionArea></affiliation></author><author><name sortKey="Murray, Jayne" sort="Murray, Jayne" uniqKey="Murray J" first="Jayne" last="Murray">Jayne Murray</name><affiliation wicri:level="1"><nlm:aff id="A12"> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW</wicri:regionArea></affiliation></author><author><name sortKey="Noguera, Rosa" sort="Noguera, Rosa" uniqKey="Noguera R" first="Rosa" last="Noguera">Rosa Noguera</name><affiliation wicri:level="1"><nlm:aff id="A7"> Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea> Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia</wicri:regionArea></affiliation></author><author><name sortKey="Pierron, Gaelle" sort="Pierron, Gaelle" uniqKey="Pierron G" first="Gaelle" last="Pierron">Gaelle Pierron</name><affiliation wicri:level="1"><nlm:aff id="A14"> Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Schleiermacher, Gudrun" sort="Schleiermacher, Gudrun" uniqKey="Schleiermacher G" first="Gudrun" last="Schleiermacher">Gudrun Schleiermacher</name><affiliation wicri:level="1"><nlm:aff id="A15"> U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Schulte, Johannes H" sort="Schulte, Johannes H" uniqKey="Schulte J" first="Johannes H." last="Schulte">Johannes H. Schulte</name><affiliation wicri:level="1"><nlm:aff id="A16"> Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, HufelandstraΔe, Essen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea> Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, HufelandstraΔe, Essen</wicri:regionArea></affiliation></author><author><name sortKey="Stallings, Ray L" sort="Stallings, Ray L" uniqKey="Stallings R" first="Ray L." last="Stallings">Ray L. Stallings</name><affiliation wicri:level="1"><nlm:aff id="A17"> National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea> National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A18"> Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, York House, Dublin, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea> Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, York House, Dublin</wicri:regionArea></affiliation></author><author><name sortKey="Tweddle, Deborah A" sort="Tweddle, Deborah A" uniqKey="Tweddle D" first="Deborah A." last="Tweddle">Deborah A. Tweddle</name><affiliation wicri:level="1"><nlm:aff id="A19"> Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne</wicri:regionArea></affiliation></author><author><name sortKey="De Preter, Katleen" sort="De Preter, Katleen" uniqKey="De Preter K" first="Katleen" last="De Preter">Katleen De Preter</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A3"> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Speleman, Frank" sort="Speleman, Frank" uniqKey="Speleman F" first="Frank" last="Speleman">Frank Speleman</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Vandesompele, Jo" sort="Vandesompele, Jo" uniqKey="Vandesompele J" first="Jo" last="Vandesompele">Jo Vandesompele</name><affiliation wicri:level="1"><nlm:aff id="A1"> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A3"> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent</wicri:regionArea></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in <italic>CCDC177</italic>, <italic>NXPH1</italic>, <italic>lnc-MRPL3-2, lnc-TREX1-1</italic> and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in <italic>SPRED3</italic>, <italic>TNFAIP2</italic>, <italic>NPM2</italic> and <italic>CYYR1</italic>) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Cohn, Sl" uniqKey="Cohn S">SL Cohn</name></author><author><name sortKey="Pearson, Adj" uniqKey="Pearson A">ADJ Pearson</name></author><author><name sortKey="London, Wb" uniqKey="London W">WB London</name></author><author><name sortKey="Monclair, T" uniqKey="Monclair T">T Monclair</name></author><author><name sortKey="Ambros, Pf" uniqKey="Ambros P">PF Ambros</name></author><author><name sortKey="Brodeur, Gm" uniqKey="Brodeur G">GM Brodeur</name></author><author><name sortKey="Faldum, A" uniqKey="Faldum A">A Faldum</name></author><author><name sortKey="Hero, B" uniqKey="Hero B">B Hero</name></author><author><name sortKey="Iehara, T" uniqKey="Iehara T">T Iehara</name></author><author><name sortKey="Machin, D" uniqKey="Machin D">D 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Oncotarget</journal-id><journal-id journal-id-type="iso-abbrev">Oncotarget</journal-id><journal-id journal-id-type="publisher-id">ImpactJ</journal-id><journal-title-group><journal-title>Oncotarget</journal-title></journal-title-group><issn pub-type="epub">1949-2553</issn><publisher><publisher-name>Impact Journals LLC</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26646589</article-id><article-id pub-id-type="pmc">4811509</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Decock</surname><given-names>Anneleen</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref><xref 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ref-type="aff" rid="A6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Laureys</surname><given-names>Geneviève</given-names></name><xref ref-type="aff" rid="A6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Van Roy</surname><given-names>Nadine</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Berbegall</surname><given-names>Ana P.</given-names></name><xref ref-type="aff" rid="A7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bienertova-Vasku</surname><given-names>Julie</given-names></name><xref ref-type="aff" rid="A8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bown</surname><given-names>Nick</given-names></name><xref ref-type="aff" rid="A9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Clément</surname><given-names>Nathalie</given-names></name><xref ref-type="aff" rid="A10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Combaret</surname><given-names>Valérie</given-names></name><xref ref-type="aff" rid="A11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haber</surname><given-names>Michelle</given-names></name><xref ref-type="aff" rid="A12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hoyoux</surname><given-names>Claire</given-names></name><xref ref-type="aff" rid="A13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Murray</surname><given-names>Jayne</given-names></name><xref ref-type="aff" rid="A12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Noguera</surname><given-names>Rosa</given-names></name><xref ref-type="aff" rid="A7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pierron</surname><given-names>Gaelle</given-names></name><xref ref-type="aff" rid="A14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schleiermacher</surname><given-names>Gudrun</given-names></name><xref ref-type="aff" rid="A15"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schulte</surname><given-names>Johannes H.</given-names></name><xref ref-type="aff" rid="A16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stallings</surname><given-names>Ray L.</given-names></name><xref ref-type="aff" rid="A17"><sup>17</sup></xref><xref ref-type="aff" rid="A18"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tweddle</surname><given-names>Deborah A.</given-names></name><xref ref-type="aff" rid="A19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><collab>for the Children's Cancer Leukaemia Group (CCLG)</collab></contrib><contrib contrib-type="author"><name><surname>De Preter</surname><given-names>Katleen</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref><xref ref-type="aff" rid="A2"><sup>2</sup></xref><xref ref-type="aff" rid="A3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Speleman</surname><given-names>Frank</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vandesompele</surname><given-names>Jo</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref><xref ref-type="aff" rid="A2"><sup>2</sup></xref><xref ref-type="aff" rid="A3"><sup>3</sup></xref></contrib></contrib-group><aff id="A1"><sup>1</sup> Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium</aff><aff id="A2"><sup>2</sup> Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium</aff><aff id="A3"><sup>3</sup> Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium</aff><aff id="A4"><sup>4</sup> DAMBI, VIB Inflammation Research Center, Technologiepark, Ghent, Belgium</aff><aff id="A5"><sup>5</sup> Department of Respiratory Medicine, Ghent University, De Pintelaan, Ghent, Belgium</aff><aff id="A6"><sup>6</sup> Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium</aff><aff id="A7"><sup>7</sup> Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain</aff><aff id="A8"><sup>8</sup> Department of Pathological Physiology, Department of Pediatric Oncology, Masaryk University, Černopolní, Brno, Czech Republic</aff><aff id="A9"><sup>9</sup> Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, United Kingdom</aff><aff id="A10"><sup>10</sup> Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France</aff><aff id="A11"><sup>11</sup> Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon, France</aff><aff id="A12"><sup>12</sup> Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia</aff><aff id="A13"><sup>13</sup> Pediatric Hemato-oncology, CHR Citadelle, Liège, Belgium</aff><aff id="A14"><sup>14</sup> Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris, France</aff><aff id="A15"><sup>15</sup> U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France</aff><aff id="A16"><sup>16</sup> Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, HufelandstraΔe, Essen, Germany</aff><aff id="A17"><sup>17</sup> National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland</aff><aff id="A18"><sup>18</sup> Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, York House, Dublin, Ireland</aff><aff id="A19"><sup>19</sup> Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom</aff><author-notes><corresp id="cor1"><bold><italic>Correspondence to:</italic></bold><italic>Jo Vandesompele,</italic><email>joke.vandesompele@ugent.be</email></corresp></author-notes><pub-date pub-type="collection"><day>12</day><month>1</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>6</day><month>12</month><year>2015</year></pub-date><volume>7</volume><issue>2</issue><fpage>1960</fpage><lpage>1972</lpage><history><date date-type="received"><day>3</day><month>8</month><year>2015</year></date><date date-type="accepted"><day>16</day><month>11</month><year>2015</year></date></history><permissions><copyright-statement>Copyright: © 2016 Decock et al.</copyright-statement><copyright-year>2016</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in <italic>CCDC177</italic>, <italic>NXPH1</italic>, <italic>lnc-MRPL3-2, lnc-TREX1-1</italic> and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in <italic>SPRED3</italic>, <italic>TNFAIP2</italic>, <italic>NPM2</italic> and <italic>CYYR1</italic>) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature.</p></abstract><kwd-group><kwd>neuroblastoma</kwd><kwd>DNA methylation</kwd><kwd>prognosis</kwd><kwd>biomarker</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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