Characterizing the Role of C19MC in the Development and Heterogeneity of ETMRs, a Lethal Childhood Brain Tumour

Embryonal tumours with multi-layered rosettes (ETMRs) are extremely clinically challenging brain tumours of infants and very young children, with characteristic rapid progression and only 10-20% overall survival. They are aggressive brain cancers characterized by recurrent amplification/genomic alterations of C19MC, a miRNA cluster on chr 19q13.42, and enrichment of LIN28A, a pluripotency factor. In this thesis, I combined experimental manipulation of C19MC together with high resolution epigenomic (Chapter 3) and genomic analyses of primary human ETMRs (Chapter 4) to delineate the role and contribution of the oncogenic C19MC miRNA cluster in ETMR transformation. My experimental studies in Chapter 3 showed that the C19MC oncogene acts partly via a complex transcriptional circuit to regulate LIN28A and MYCN oncogene expression. Using detailed epigenomic analyses, I uncovered a novel super-enhancer resulting from the known TTHY1-C19MC fusion which potently drives C19MC expression. I further showed that MYCN, which is upregulated via long-range DNA: DNA interactions, drives a core transcriptional regulatory circuit (CRC) that impinges on the C19MC-associated super-enhancer. Importantly, I demonstrated that treatment of ETMR cells with the bromodomain inhibitor JQ1 abrogated the CRC and led to ETMR cell death. These findings together with our observations that C19MC and LIN28A regulate expression of embryonic DNMT3A/B, indicates C19MC acts in part via a self-reinforcing C19MC-LIN28-MYCN oncogenic circuit to maintain a highly primitive transformed cell state in ETMRs. In Chapter 4, I performed whole genome sequencing and RNA-seq analysis of 68 primary ETMRs and discovered that a majority (98%) of ETMRs have defects in DNA Damage Response Pathways – 74% of tumours had alterations of genes in the homologous recombination (HR) pathway while other DNA damage repair pathways genes, including TP53, mismatch repair, nucleotide excision repair and base excision repair were observed in the remainder. Consistently, I discovered that the majority of ETMRs exhibit mutational signature 3, which is attributed to mutations in canonical DNA repair. Additionally, I show that a large proportion of ETMRs exhibit genomic instability, characterised by structural variations and chromothripsis, which is most frequently found within the C19MC-TTYH1 region. Collectively, my results point to significant genomic heterogeneity in ETMRs.

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