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dc.contributor.authorNordlund, Jessica
dc.contributor.authorBäcklin, Christofer L
dc.contributor.authorZachariadis, Vasilios
dc.contributor.authorCavelier, Lucia
dc.contributor.authorDahlberg, Johan
dc.contributor.authorÖfverholm, Ingegerd
dc.contributor.authorBarbany, Gisela
dc.contributor.authorNordgren, Ann
dc.contributor.authorÖvernäs, Elin
dc.contributor.authorAbrahamsson, Jonas
dc.contributor.authorFlaegstad, Trond
dc.contributor.authorHeyman, Mats M
dc.contributor.authorJónsson, Ólafur G
dc.contributor.authorKanerva, Jukka
dc.contributor.authorLarsson, Rolf
dc.contributor.authorPalle, Josefine
dc.contributor.authorSchmiegelow, Kjeld
dc.contributor.authorGustafsson, Mats G
dc.contributor.authorLönnerholm, Gudmar
dc.contributor.authorForestier, Erik
dc.contributor.authorSyvänen, Ann-Christine
dc.date.accessioned2015-06-25T11:48:23Zen
dc.date.available2015-06-25T11:48:23Zen
dc.date.issued2015en
dc.date.submitted2015en
dc.identifier.citationClin Epigenetics 2015, 7 (1):11en
dc.identifier.issn1868-7075en
dc.identifier.pmid25729447en
dc.identifier.doi10.1186/s13148-014-0039-zen
dc.identifier.urihttp://hdl.handle.net/2336/558505en
dc.descriptionTo access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.en
dc.description.abstractWe present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL.
dc.description.abstractWe used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations ('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5.
dc.description.abstractOur findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.
dc.description.sponsorshipSwedish Foundation for Strategic Research RBc08-008 Swedish Cancer Society CAN2010/592 Swedish Childhood Cancer Foundation 11098 Swedish Research Council for Science and Technology 90559401 Swedish Research Council FORTE Swedish Research Council FORMAS Swedish Research Council VINNOVA Swedish Research Council VR 259-2012-23en
dc.language.isoenen
dc.publisherBioMed Central Ltden
dc.relation.urlhttp://dx.doi.org/10.1186/s13148-014-0039-zen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343276/en
dc.rightsArchived with thanks to Clinical epigeneticsen
dc.rightsopenAccessen
dc.subjectHvítblæðien
dc.subject.meshCytogeneticsen
dc.subject.meshDNA Methylationen
dc.subject.meshPrecursor Cell Lymphoblastic Leukemia-Lymphomaen
dc.subject.meshImmunophenotypingen
dc.subject.meshEpigenomicsen
dc.titleDNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Box 1432, BMC, SE-751 44 Uppsala, Sweden. 2Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, Entrance 40, SE-751 85 Uppsala, Sweden. 3Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden. 4Department of Immunology, Genetics and Pathology, Uppsala University, Rudbecklaboratoriet, SE-751 85 Uppsala, Sweden. 5Department of Pediatrics, Queen Silvia Children's Hospital, Rondvägen 10, SE-416 85 Gothenburg, Sweden. 6Department of Pediatrics, Tromsø University and University Hospital, Sykehusveien 38, N-9038 Tromsø, Norway. 7Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Q6:05, SE-171 76, Stockholm, Sweden. 8Pediatric Hematology-Oncology, Children's Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Norðurmýri, 101, Reykjavik, Iceland. 9Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Box 281, FIN-00029 Helsinki, Finland. 10Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Box 1432, BMC, SE-751 44 Uppsala, Sweden ; Department of Women's and Children's Health, Pediatric Oncology, Uppsala University, Uppsala University Hospital, Entrance 95, SE-751 85 Uppsala, Sweden. 11Pediatrics and Adolescent Medicine, Rigshospitalet, and the Medical Faculty, Institute of Clinical Medicine, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. 12Department of Women's and Children's Health, Pediatric Oncology, Uppsala University, Uppsala University Hospital, Entrance 95, SE-751 85 Uppsala, Sweden. 13Department of Medical Biosciences, University of Umeå, SE-901 85 Umeå, Sweden.en
dc.identifier.journalClinical epigeneticsen
dc.rights.accessOpen Accessen
refterms.dateFOA2018-09-12T15:16:54Z
html.description.abstractWe present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL.
html.description.abstractWe used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations ('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5.
html.description.abstractOur findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.


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