Poster Presentation 25th Lorne Cancer Conference 2013

DNA methylation patterns in pediatric Acute Lymphoblastic Leukemia (#142)

Zac Chatterton 1 , Leah Morenos 1 , Franciose Mechinaud 2 , Minhee Halemba 1 , Jeff Craig 1 , Mandy Parkinson-bates 1 , David Ashley 3 , Jane Ng 1 , Richard Saffery 1 , Nick Wong 1
  1. Murdoch Childrens Research Institute, Parkville, VIC, Australia
  2. Childrens Cancer Centre, Royal Childrens Hospital, Melbourne, VIC, Australia
  3. Barwon Health, Geelong, VIC, Australia

Pediatric Acute Lymphoblastic Leukemia represents a success story of modern cancer intervention with > 85% of patients achieving a 5-year event free survival in developed countries. Intensified treatment regimes have improved cure rates, however the cytotoxicity of agents used in therapy have adverse side effects. Targeted therapeutics has the potential to reduce side effects and improve cure rates, although progress is inhibited by knowledge gaps in the biological underpinnings of leukemia.

Similar to all cancers, ALL demonstrates epigenetic disruption. Such disruptions can contribute to oncogenesis and could fill knowledge gaps where recurrent genetic mutations are often insufficient to cause clinically overt leukemia. DNA methylation is the best understood epigenetic modification and disruption of the DNA methylation profile is a feature of most cancers. Research using candidate gene approaches has shown a regularly occurring phenomenon of aberrant DNA methylation patterns across numerous CpG islands in the genomes of ALL patients.

We profiled genome-wide DNA methylation changes in pediatric ALL patients using the Infinium 27k and 450k methylation microarrays with independent validation through SEQUENOM EpiTYPER. Promoter hypermethylation was a prominent feature effecting genes implicated in cancer, hematopoietic development and many novel genes. Furthermore we discovered promoter hypo- and hyper-methylation patterns specific to several genetic subtypes of pediatric ALL that were strongly correlated with gene expression data. These aberrant DNA methylation loci represent PCR amplifiable targets for disease tracking with potential implications in leukemia development and drug resistance. Furthermore, the genes we have identified represent targets for therapeutic intervention, reducing the burden of chemotherapy toxicity on affected children, and moving us towards a curable disease