DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia

2.50
Hdl Handle:
http://hdl.handle.net/2336/97678
Title:
DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia
Authors:
Milani, Lili; Lundmark, Anders; Kiialainen, Anna; Nordlund, Jessica; Flaegstad, Trond; Forestier, Erik; Heyman, Mats; Jonmundsson, Gudmundur; Kanerva, Jukka; Schmiegelow, Kjeld; Söderhäll, Stefan; Gustafsson, Mats G; Lönnerholm, Gudmar; Syvänen, Ann-Christine
Citation:
Blood 2010, 115(6):1214-25
Issue Date:
11-Feb-2010
Abstract:
Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320 CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve stratification of ALL patients. The genes highlighted in our study are not enriched to specific pathways, but the gene expression levels are inversely correlated to the methylation levels.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://dx.doi.org/10.1182/blood-2009-04-214668

Full metadata record

DC FieldValue Language
dc.contributor.authorMilani, Lilien
dc.contributor.authorLundmark, Andersen
dc.contributor.authorKiialainen, Annaen
dc.contributor.authorNordlund, Jessicaen
dc.contributor.authorFlaegstad, Tronden
dc.contributor.authorForestier, Eriken
dc.contributor.authorHeyman, Matsen
dc.contributor.authorJonmundsson, Gudmunduren
dc.contributor.authorKanerva, Jukkaen
dc.contributor.authorSchmiegelow, Kjelden
dc.contributor.authorSöderhäll, Stefanen
dc.contributor.authorGustafsson, Mats Gen
dc.contributor.authorLönnerholm, Gudmaren
dc.contributor.authorSyvänen, Ann-Christineen
dc.date.accessioned2010-04-29T14:25:08Z-
dc.date.available2010-04-29T14:25:08Z-
dc.date.issued2010-02-11-
dc.date.submitted2010-04-29-
dc.identifier.citationBlood 2010, 115(6):1214-25en
dc.identifier.issn1528-0020-
dc.identifier.pmid19965625-
dc.identifier.doi10.1182/blood-2009-04-214668-
dc.identifier.urihttp://hdl.handle.net/2336/97678-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractDespite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320 CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve stratification of ALL patients. The genes highlighted in our study are not enriched to specific pathways, but the gene expression levels are inversely correlated to the methylation levels.en
dc.language.isoenen
dc.publisherAmerican Society of Hematologyen
dc.relation.urlhttp://dx.doi.org/10.1182/blood-2009-04-214668en
dc.subject.meshAdolescenten
dc.subject.meshB-Lymphocytesen
dc.subject.meshChilden
dc.subject.meshChild, Preschoolen
dc.subject.meshChromosomes, Human, Pair 12en
dc.subject.meshChromosomes, Human, Pair 21en
dc.subject.meshCpG Islandsen
dc.subject.meshDNA Methylationen
dc.subject.meshDNA, Neoplasmen
dc.subject.meshFemaleen
dc.subject.meshGene Expression Profilingen
dc.subject.meshGene Expression Regulation, Leukemicen
dc.subject.meshHumansen
dc.subject.meshInfanten
dc.subject.meshInfant, Newbornen
dc.subject.meshMaleen
dc.subject.meshNeoplasm Proteinsen
dc.subject.meshPolymerase Chain Reactionen
dc.subject.meshPrecursor Cell Lymphoblastic Leukemia-Lymphomaen
dc.subject.meshPrognosisen
dc.subject.meshTreatment Outcomeen
dc.titleDNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemiaen
dc.typeArticleen
dc.contributor.departmentMolecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.en
dc.identifier.journalBlooden

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