Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia

Alem S. Gabriel, Fadhel M. Laftay, Edward C. Schwalbe, Sirintra Nakjang, Simon J. Cockell, Alice Iliasova, Amir Enshaei, Claire Schwab, Vikki Rand, Steven C. Clifford, Sally E. Kinsey, Chris D. Mitchell, Ajay Vora, Christine J. Harrison, Anthony Moorman, Gordon Strathdee

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)717-726
Number of pages10
JournalEpigenetics
Volume10
Issue number8
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Epigenomics
DNA Methylation
Recurrence
Polyploidy
Computational Biology
Methylation
Genes
Cluster Analysis
Immunity
Biomarkers
Genome
Ligands
Survival
Infection

Keywords

  • 450K
  • ALL
  • Biomarker
  • Childhood
  • Methylation
  • Relapse

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Gabriel, A. S., Laftay, F. M., Schwalbe, E. C., Nakjang, S., Cockell, S. J., Iliasova, A., ... Strathdee, G. (2015). Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia. Epigenetics, 10(8), 717-726. https://doi.org/10.1080/15592294.2015.1061174

Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia. / Gabriel, Alem S.; Laftay, Fadhel M.; Schwalbe, Edward C.; Nakjang, Sirintra; Cockell, Simon J.; Iliasova, Alice; Enshaei, Amir; Schwab, Claire; Rand, Vikki; Clifford, Steven C.; Kinsey, Sally E.; Mitchell, Chris D.; Vora, Ajay; Harrison, Christine J.; Moorman, Anthony; Strathdee, Gordon.

In: Epigenetics, Vol. 10, No. 8, 01.01.2015, p. 717-726.

Research output: Contribution to journalArticle

Gabriel, AS, Laftay, FM, Schwalbe, EC, Nakjang, S, Cockell, SJ, Iliasova, A, Enshaei, A, Schwab, C, Rand, V, Clifford, SC, Kinsey, SE, Mitchell, CD, Vora, A, Harrison, CJ, Moorman, A & Strathdee, G 2015, 'Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia', Epigenetics, vol. 10, no. 8, pp. 717-726. https://doi.org/10.1080/15592294.2015.1061174
Gabriel, Alem S. ; Laftay, Fadhel M. ; Schwalbe, Edward C. ; Nakjang, Sirintra ; Cockell, Simon J. ; Iliasova, Alice ; Enshaei, Amir ; Schwab, Claire ; Rand, Vikki ; Clifford, Steven C. ; Kinsey, Sally E. ; Mitchell, Chris D. ; Vora, Ajay ; Harrison, Christine J. ; Moorman, Anthony ; Strathdee, Gordon. / Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia. In: Epigenetics. 2015 ; Vol. 10, No. 8. pp. 717-726.
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