Methylation profiling of paediatric pilocytic astrocytoma reveals variants specifically associated with tumour location and predictive of recurrence

Abstract

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 5404 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, which 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.

Integrated DNA methylation analysis identifies topographical and tumoral biomarkers in pilocytic astrocytomas

“…This finding was supported by the identification of distinct gene expression [ 5 , 15 – 20 ] and methylation profiles [ 5 , 20 , 21 ] between tumors having different localizations. Sharma et al [ 16 ] described a specific gene expression pattern discriminating infratentorial and supratentorial PAs.…”

Dysembryoplastic neuroepithelial tumor-like pilocytic astrocytoma

“…[ 5 ] Approximately 5% to 10% PAs are associated with neurofibromatosis type 1 (NF1), especially those cases which arise in the optic/chiasmatic region. [ 6 ] PAs mainly involve the neuraxis, such as cerebellum, optic pathway, hypothalamus, brainstem, and spinal cord, while the supratentorial region is also frequently encountered. [ 3 , 6 ] Clinical manifestations of PAs are dependent on the lesion locations.…”

“…[ 6 ] PAs mainly involve the neuraxis, such as cerebellum, optic pathway, hypothalamus, brainstem, and spinal cord, while the supratentorial region is also frequently encountered. [ 3 , 6 ] Clinical manifestations of PAs are dependent on the lesion locations. Neuroradiologically, PAs typically show hypo- or iso-intense lesion on T1-weighted images with enhancement and hyperintense on T2-weighted images.…”

“…[ 11 ] Moreover, aberrant DNA methylation has been studied in PAs, which varied according to tumor locations as well. [ 6 ]…”

The age of adult pilocytic astrocytoma cells

“…In children, methylation profiles of PAs have been linked to tumor behavior. DNA methylation profiles specific to PA location and predictive of clinical behavior were reported recently [ 9 ]. However, this study did not include adult PA patients and was limited to discrimination between infants and non-infants.…”