DNA methylation is a process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging and carcinogenesis.
One of the first and most important epigenetic modifications studied in humans is DNA methylation, which describes the covalent addition of a methyl group preferentially at the 5′-position of a cytosine or guanine nucleotide. These CpG dinucleotides tend to cluster to so-called CpG islands, being located in the promoter regions of more than half of all human genes, or to CpG island shores, which are regions of lower CpG density that lie in close proximity to CpG islands 1) 2).
Childhood pilocytic astrocytomas (PA) are low grade tumours with an excellent prognosis. However, a minority, particularly those in surgically inaccessible locations, have poorer long term outcome. At present it is unclear whether anatomical location in isolation, or in combination with underlying biological variation, determines clinical behaviour. Here we have tested the utility of DNA methylation profiling to inform tumour biology and to predict behaviour in paediatric PA. Genome-wide DNA methylation profiles were generated for 117 paediatric PAs. Using a combination of analyses we identified DNA methylation variants specific to tumour location and predictive of behaviour. Receiver operating characteristic analysis was used to test the predictive utility of clinical and/or DNA methylation features to classify tumour behaviour at diagnosis. Unsupervised analysis distinguished three methylation clusters associated with tumour location (cortical, midline, and infratentorial). Differential methylation of 5,404 sites identified enrichment of genes involved in 'embryonic nervous system development'. Specific hypermethylation of NEUROG1 and NR2E1 was identified as a feature of cortical tumours. A highly accurate method to classify tumours according to behaviour, that combined three clinical features (age, location and extent of resection) and methylation level at a single site, was identified. Our findings show location-specific epigenetic profiles for PAs, potentially reflecting their cell type of origin. This may account for differences in clinical behaviour according to location independent of histopathology. We also defined an accurate method to predict tumour behaviour at diagnosis. This warrants further testing in similar patient cohorts 4).