Unmasking Novel Epigenetic Mechanisms of Medulloblastoma Pathogenesis

The leading cause of cancer-related death in children is due to brain tumours. Medulloblastoma is the most common malignant paediatric brain tumour, representing 20% of childhood brain malignancies. Despite current multimodal therapies, there remains significant treatment-induced morbidity. We therefore require a greater understanding of medulloblastoma pathogenesis to further stratify those patients that require aggressive treatment and those in which milder regiments can be implemented. The aim of this thesis is to unravel the molecular underpinnings of childhood medulloblastoma. To date, our lab has re-conceptualized the genetic landscape of medulloblastoma by demonstrating that it is a heterogeneous disease with multiple distinct molecular subgroups. These different subgroups are currently treated the same, but have vastly different prognosis and patient characteristics. In the first half of this thesis, I attempt to address the question whether medulloblastoma subgroups remain stable between the primary and metastatic compartments. This has significant implications on clinical management given the advent of targeted, subgroup-based therapies. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are retained during metastatic progression. Given the paucity of recurrent somatic mutations found to date using sequencing technologies, much effort has gone into understanding the epigenetic mechanisms that drive medulloblastoma formation. In the latter half of this thesis, I present data to support the identification of a previously well studied hypermethylated locus on 17p13.3 harbouring a newly described bidirectional promoter. This locus is frequently methylated and rarely mutated in cancer, suggesting a clonal selection towards hypermethylation. Further characterization of this locus reveals a novel tumor suppressor microRNA cluster miR-212/132 in the pathogenesis of medulloblastoma. Re-expression of this endogenously methylated locus using RNA-guided gene activation with CRISPR-Cas9 technology decreased tumour proliferation in vitro and in vivo; this approach may represent new therapeutic options in the fight against cancer.Ph.D.2017-11-30 00:00:0