Year: 2016
Type: dissertation
Study design: Observational Study
Abstract: CNS rhabdoid tumours (ATRTs) are lethal childhood cancers with SMARCB1 loss as the only reported recurrent alteration in a remarkably stable genome. ATRTs exhibit substantial clinical heterogeneity which has made therapeutic advances challenging. To uncover the molecular basis for clinical heterogeneity in ATRTs, this thesis undertook transcriptional profiling of ATRTs, which demonstrated that ATRTs encompassed two broad transcriptional subgroups, which correlated with distinct clinical phenotypes. Group 1 ATRT, had a proneural signature, upregulation of NOTCH signalling, and predominant supratentorial location, correlated with superior survival with radiation-free treatments. While group 2 ATRTs are characterized by mesenchymal signalling, increased BMP expression and infratentorial locations, correlated with more aggressive disease phenotype and poor survival despite high-dose chemo-radiotherapy regimens. I further investigated mechanisms of differential therapeutic outcomes in ATRTs, by performing an integrated multiplatform epi-genomic analysis of a large cohort of ATRTs. These studies showed ATRT coding regions were predominantly targeted by structural mechanisms and identified novel coding alterations that targeted loci with functions in neural development and epigenetic regulation in up to 20% of ATRTs. Using methylation and chromatin openness profiling, I demonstrated that group 2 ATRTs could be further segregated into subtypes 2A and 2B with distinct clinical associations. Group 2A comprised predominantly infratentorial tumours arising in very young patients, while group 2B comprised spinal as well as supra and infratentorial tumours arising in all ages. The chromatin landscapes of ATRT subtypes also correlated with distinct therapeutic sensitivities of subgroup-specific ATRT cell lines to a panel of signalling and epigenetic inhibitors. Significantly, I discovered that differential methylation of a novel PDGFRβ-associated enhancer element confers robust sensitivity to Dasatinib and Nilotinib in group 2 ATRTs. Collectively, my thesis demonstrate that ATRTs can be segregated into 3 molecular subtypes with different therapeutic profiles, and provides important rationale for therapeutic stratification of ATRTs patients.
Source: TSpace (University of Toronto)
Author: Jonathon Torchia
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2807523195