Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma.
Identifieur interne : 002449 ( PubMed/Curation ); précédent : 002448; suivant : 002450Methyl-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 ] ; 2016.
Descripteurs français
- KwdFr :
- ADN tumoral (génétique), Biologie informatique, Cellules cancéreuses en culture, Femelle, Humains, Ilots CpG (génétique), Marqueurs biologiques (analyse), Mâle, Méthylation de l'ADN, Neuroblastome (diagnostic), Neuroblastome (génétique), Nourrisson, Pronostic, Réaction de polymérisation en chaine en temps réel, Sites de fixation, Stade de la tumeur, Études de cohortes.
- MESH :
- analyse : Marqueurs biologiques.
- diagnostic : Neuroblastome.
- génétique : ADN tumoral, Ilots CpG, Neuroblastome.
- Biologie informatique, Cellules cancéreuses en culture, Femelle, Humains, Mâle, Méthylation de l'ADN, Nourrisson, Pronostic, Réaction de polymérisation en chaine en temps réel, Sites de fixation, Stade de la tumeur, Études de cohortes.
English descriptors
- KwdEn :
- Binding Sites, Biomarkers (analysis), Cohort Studies, Computational Biology, CpG Islands (genetics), DNA Methylation, DNA, Neoplasm (genetics), Female, Humans, Infant, Male, Neoplasm Staging, Neuroblastoma (diagnosis), Neuroblastoma (genetics), Prognosis, Real-Time Polymerase Chain Reaction, Tumor Cells, Cultured.
- MESH :
- chemical , analysis : Biomarkers.
- diagnosis : Neuroblastoma.
- genetics : CpG Islands, DNA, Neoplasm, Neuroblastoma.
- Binding Sites, Cohort Studies, Computational Biology, DNA Methylation, Female, Humans, Infant, Male, Neoplasm Staging, Prognosis, Real-Time Polymerase Chain Reaction, Tumor Cells, Cultured.
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 CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) 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.
DOI: 10.18632/oncotarget.6477
PubMed: 26646589
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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:affiliation>Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, United Kingdom.</nlm:affiliation><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:affiliation>Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France.</nlm:affiliation><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:affiliation>Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon, France.</nlm:affiliation><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:affiliation>Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia.</nlm:affiliation><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 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of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain.</nlm:affiliation><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:affiliation>Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris, France.</nlm:affiliation><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:affiliation>U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France.</nlm:affiliation><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:affiliation>Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstraße, Essen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstraße, 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:affiliation>National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.</nlm:affiliation><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></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:affiliation>Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.</nlm:affiliation><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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, 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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, 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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:26646589</idno><idno type="pmid">26646589</idno><idno type="doi">10.18632/oncotarget.6477</idno><idno type="wicri:Area/PubMed/Corpus">002517</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002517</idno><idno type="wicri:Area/PubMed/Curation">002449</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002449</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, 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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, 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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, 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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, 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:affiliation>Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium.</nlm:affiliation><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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, 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:affiliation>Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain.</nlm:affiliation><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:affiliation>Department of Pathological Physiology, Department of Pediatric Oncology, Masaryk University, Černopolní, Brno, Czech Republic.</nlm:affiliation><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:affiliation>Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, United Kingdom.</nlm:affiliation><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:affiliation>Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France.</nlm:affiliation><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:affiliation>Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon, France.</nlm:affiliation><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:affiliation>Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia.</nlm:affiliation><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:affiliation>Pediatric Hemato-oncology, CHR Citadelle, Liège, Belgium.</nlm:affiliation><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:affiliation>Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia.</nlm:affiliation><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:affiliation>Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain.</nlm:affiliation><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:affiliation>Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris, France.</nlm:affiliation><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:affiliation>U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France.</nlm:affiliation><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:affiliation>Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstraße, Essen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstraße, 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:affiliation>National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.</nlm:affiliation><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></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:affiliation>Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.</nlm:affiliation><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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, 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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, 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:affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent</wicri:regionArea></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Binding Sites</term><term>Biomarkers (analysis)</term><term>Cohort Studies</term><term>Computational Biology</term><term>CpG Islands (genetics)</term><term>DNA Methylation</term><term>DNA, Neoplasm (genetics)</term><term>Female</term><term>Humans</term><term>Infant</term><term>Male</term><term>Neoplasm Staging</term><term>Neuroblastoma (diagnosis)</term><term>Neuroblastoma (genetics)</term><term>Prognosis</term><term>Real-Time Polymerase Chain Reaction</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN tumoral (génétique)</term><term>Biologie informatique</term><term>Cellules cancéreuses en culture</term><term>Femelle</term><term>Humains</term><term>Ilots CpG (génétique)</term><term>Marqueurs biologiques (analyse)</term><term>Mâle</term><term>Méthylation de l'ADN</term><term>Neuroblastome (diagnostic)</term><term>Neuroblastome (génétique)</term><term>Nourrisson</term><term>Pronostic</term><term>Réaction de polymérisation en chaine en temps réel</term><term>Sites de fixation</term><term>Stade de la tumeur</term><term>Études de cohortes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Biomarkers</term></keywords><keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>Marqueurs biologiques</term></keywords><keywords scheme="MESH" qualifier="diagnosis" xml:lang="en"><term>Neuroblastoma</term></keywords><keywords scheme="MESH" qualifier="diagnostic" xml:lang="fr"><term>Neuroblastome</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>CpG Islands</term><term>DNA, Neoplasm</term><term>Neuroblastoma</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ADN tumoral</term><term>Ilots CpG</term><term>Neuroblastome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Cohort Studies</term><term>Computational Biology</term><term>DNA Methylation</term><term>Female</term><term>Humans</term><term>Infant</term><term>Male</term><term>Neoplasm Staging</term><term>Prognosis</term><term>Real-Time Polymerase Chain Reaction</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Biologie informatique</term><term>Cellules cancéreuses en culture</term><term>Femelle</term><term>Humains</term><term>Mâle</term><term>Méthylation de l'ADN</term><term>Nourrisson</term><term>Pronostic</term><term>Réaction de polymérisation en chaine en temps réel</term><term>Sites de fixation</term><term>Stade de la tumeur</term><term>Études de cohortes</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) 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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26646589</PMID><DateCreated><Year>2016</Year><Month>02</Month><Day>16</Day></DateCreated><DateCompleted><Year>2016</Year><Month>12</Month><Day>13</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN><JournalIssue CitedMedium="Internet"><Volume>7</Volume><Issue>2</Issue><PubDate><Year>2016</Year><Month>Jan</Month><Day>12</Day></PubDate></JournalIssue><Title>Oncotarget</Title><ISOAbbreviation>Oncotarget</ISOAbbreviation></Journal><ArticleTitle>Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma.</ArticleTitle><Pagination><MedlinePgn>1960-72</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.18632/oncotarget.6477</ELocationID><Abstract><AbstractText>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 CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) 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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Decock</LastName><ForeName>Anneleen</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ongenaert</LastName><ForeName>Maté</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cannoodt</LastName><ForeName>Robrecht</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>DAMBI, VIB Inflammation Research Center, Technologiepark, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Respiratory Medicine, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Verniers</LastName><ForeName>Kimberly</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Wilde</LastName><ForeName>Bram</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Laureys</LastName><ForeName>Geneviève</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Van Roy</LastName><ForeName>Nadine</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Berbegall</LastName><ForeName>Ana P</ForeName><Initials>AP</Initials><AffiliationInfo><Affiliation>Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bienertova-Vasku</LastName><ForeName>Julie</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Pathological Physiology, Department of Pediatric Oncology, Masaryk University, Černopolní, Brno, Czech Republic.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bown</LastName><ForeName>Nick</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Clément</LastName><ForeName>Nathalie</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Combaret</LastName><ForeName>Valérie</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Centre Léon Bérard, Laboratoire de Recherche Translationnelle, rue Laennec, Lyon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haber</LastName><ForeName>Michelle</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hoyoux</LastName><ForeName>Claire</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Pediatric Hemato-oncology, CHR Citadelle, Liège, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Murray</LastName><ForeName>Jayne</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick NSW, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Noguera</LastName><ForeName>Rosa</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Pathology, Medical School, University of Valencia, and Health Research Institute INCLIVA, Blasco Ibañez, Valencia, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pierron</LastName><ForeName>Gaelle</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Unité de Génétique Somatique, Institut Curie, rue d'Ulm, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schleiermacher</LastName><ForeName>Gudrun</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, rue d'Ulm, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schulte</LastName><ForeName>Johannes H</ForeName><Initials>JH</Initials><AffiliationInfo><Affiliation>Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstraße, Essen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stallings</LastName><ForeName>Ray L</ForeName><Initials>RL</Initials><AffiliationInfo><Affiliation>National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, York House, Dublin, Ireland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tweddle</LastName><ForeName>Deborah A</ForeName><Initials>DA</Initials><AffiliationInfo><Affiliation>Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><CollectiveName>Children’s Cancer and Leukaemia Group (CCLG)</CollectiveName></Author><Author ValidYN="Y"><LastName>De Preter</LastName><ForeName>Katleen</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Speleman</LastName><ForeName>Frank</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vandesompele</LastName><ForeName>Jo</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Center for Medical Genetics, Ghent University, De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Cancer Research Institute Ghent (CRIG), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Bioinformatics Institute Ghent From Nucleotides to Networks (BIG N2N), De Pintelaan, Ghent, Belgium.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 CA127496</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>5R01CA127496</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><Agency>Cancer Research UK</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016448">Multicenter Study</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United 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MajorTopicYN="N">Cohort Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019295" MajorTopicYN="N">Computational Biology</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018899" MajorTopicYN="N">CpG Islands</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019175" MajorTopicYN="Y">DNA Methylation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004273" MajorTopicYN="N">DNA, Neoplasm</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007223" MajorTopicYN="N">Infant</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009367" MajorTopicYN="N">Neoplasm Staging</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009447" MajorTopicYN="N">Neuroblastoma</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="Y">diagnosis</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011379" MajorTopicYN="N">Prognosis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D060888" MajorTopicYN="N">Real-Time Polymerase Chain Reaction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014407" MajorTopicYN="N">Tumor Cells, Cultured</DescriptorName></MeshHeading></MeshHeadingList><OtherID Source="NLM">PMC4811509</OtherID><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">DNA methylation</Keyword><Keyword MajorTopicYN="N">biomarker</Keyword><Keyword MajorTopicYN="N">neuroblastoma</Keyword><Keyword MajorTopicYN="N">prognosis</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>08</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>11</Month><Day>16</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>12</Month><Day>10</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>12</Month><Day>10</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26646589</ArticleId><ArticleId IdType="pii">6477</ArticleId><ArticleId IdType="doi">10.18632/oncotarget.6477</ArticleId><ArticleId IdType="pmc">PMC4811509</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour 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