title: Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia.
abstract: Although children with acute lymphoblastic leukemia (ALL) generally have a good outcome, some patients do relapse and survival following relapse is poor. Altered DNA methylation is highly prevalent in ALL and raises the possibility that DNA methylation-based biomarkers could predict patient outcome. In this study, genome-wide methylation analysis, using the Illumina Infinium HumanMethylation450 BeadChip platform, was carried out on 52 diagnostic patient samples from 4 genetic subtypes [ETV6-RUNX1, high hyperdiploidy (HeH), TCF3-PBX1 and dic(9;20)(p11-13;q11)] in a 1:1 case-control design with patients who went on to relapse (as cases) and patients achieving long-term remission (as controls). Pyrosequencing assays for selected loci were used to confirm the array-generated data. Non-negative matrix factorization consensus clustering readily clustered samples according to genetic subgroups and gene enrichment pathway analysis suggested that this is in part driven by epigenetic disruption of subtype specific signaling pathways. Multiple bioinformatics approaches (including bump hunting and individual locus analysis) were used to identify CpG sites or regions associated with outcome. However, no associations with relapse were identified. Our data revealed that ETV6-RUNX1 and dic(9;20) subtypes were mostly associated with hypermethylation; conversely, TCF3-PBX1 and HeH were associated with hypomethylation. We observed significant enrichment of the neuroactive ligand-receptor interaction pathway in TCF3-PBX1 as well as an enrichment of genes involved in immunity and infection pathways in ETV6-RUNX1 subtype. Taken together, our results suggest that altered DNA methylation may have differential impacts in distinct ALL genetic subtypes.
authors.affiliation: a Northern Institute for Cancer Research; Faculty of Medical Sciences; Newcastle University ; Newcastle upon Tyne , UK.
authors.forename: Alem S
authors.initials: AS
authors.lastname: Gabriel
authors.forename: Fadhel M
authors.initials: FM
authors.lastname: Lafta
authors.forename: Edward C
authors.initials: EC
authors.lastname: Schwalbe
authors.forename: Sirintra
authors.initials: S
authors.lastname: Nakjang
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cockell
authors.forename: Alice
authors.initials: A
authors.lastname: Iliasova
authors.forename: Amir
authors.initials: A
authors.lastname: Enshaei
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.forename: Vikki
authors.initials: V
authors.lastname: Rand
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.forename: Sally E
authors.initials: SE
authors.lastname: Kinsey
authors.forename: Chris D
authors.initials: CD
authors.lastname: Mitchell
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.forename: Gordon
authors.initials: G
authors.lastname: Strathdee
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D057890:Epigenomics; D015894:Genome, Human; D006801:Humans; D007223:Infant; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012008:Recurrence; D012097:Repressor Proteins / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C493728:RUNX1 protein, human; C407909:TCF3 protein, human; C083400:PBX1 protein, human
keywords: 450K; ALL; biomarker; childhood; methylation; relapse