DNA Methylation Profiling of Childhood Acute Lymphoblastic Leukaemia Using Illumina Infinium DNA Methylation27 Bead Arrays Identifies a Distinct DNA Methylation Signature Associated with Leukaemogenesis

Abstract 4650

Acute Lymphoblastic Leukaemia (ALL) is the most common form of cancer in children. Although up to 80% of cases can be characterised by either abnormal chromosome number (hyper- or hypo-diploidy) or a specific chromosome translocation, a significant proportion of cases do no exhibit any major chromosome abnormality. Indeed, no common gene mutation has been found to be associated with childhood leukaemia. This suggests that epigenetic modifications, in particular DNA methylation, may also play a significant role in ALL pathogenesis. Understanding the specific epigenetic changes associated with this disease is therefore of paramount importance for predicting onset and disease outcome and understanding disease aetiology.

From our cohort of over 450 cases of childhood leukaemia we analysed 12 cases of childhood ALL that carried the TEL/AML1 (RUNX1/ETV6) chromosome translocation using Illumina Infinium Human Methylation27K bead chip arrays. These interrogate 27,578 CpG methylation sites across the human genome covering 14,495 RefSeq gene promoters. We analysed matching leukaemia and remission bone marrow with the aim of identifying DNA methylation signatures associated with this leukaemia subtype.

We used a number of computational methods to determine the DNA methylation signatures associated with childhood ALL including LIMMA, Centroid Analysis and Support Vector Machine Modelling. This identified 16 probes sufficient to define a leukaemia sample from a remission sample based on methylation level.

We are currently validating our results using high throughput SEQUENOM and performing gene pathway and network analyses to look for commonly affected genes associated with leukaemia. These methylation changes we have identified may help refine the diagnosis of childhood ALL and identify cellular pathways subject to epigenetic disruption in ALL.