Low-grade glioma, or LGG, are central nervous system tumours with very few genetic alterations. Typically in children, these tumours do not transform into a more malignant tumour such as glioblastoma. However, if tumours do transform the prognosis is universally fatal. Because of the dismal prognosis of tumour transformation, and the significant morbidity associated with the treatment of unresectable LGGs, it is critical to develop novel therapeutic approaches.
Our hypothesis is that novel epigenetic and genetic events arise during tumour progression and drive continual growth and/or transformation. These events are potentially good candidates for targeted therapies. Our aim is to unravel these driver events by using a genome-wide approach and by looking at alterations both at a genetic (whole-exome) and an epigenetic (DNA methylation array) level. Eleven formalin-fixed paraffin-embedded tissue samples from four patients with low to high-grade tumour transformation were subject to whole-exome sequencing (Agilent Sure Select All Exome V6) and genome-wide DNA methylation array analysis (Illumina HumanMethylation EPIC array). Patient samples consisted of a primary diagnostic low-grade glioma and malignant transformation sample. Two patients had additional tumour recurrences between diagnosis and transformation which were also examined.
Genomic analysis demonstrated relatively few sequence changes between primary and transformed tumours, however changes in copy number profile were common, particularly deletion of CDKN2A. Analysis of DNA methylation data showed extensive changes in DNA methylation profile between low and high-grade tumours, however few genes were consistently differentially methylated across the cohort suggesting transformation may be driven by unique patient-specific events.