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Molecular characterization of rhabdoid tumours from multiple anatomical sites Chun, Hye-Jung Elizabeth

Abstract

Rhabdoid tumours (RTs) are highly aggressive paediatric cancers that predominantly affect infants, with an overall 4-year survival rate below 25% and no curative therapy established to date. Nearly all RTs exhibit pathognomonic loss of SMARCB1, a core subunit of the SWI/SNF complex that mobilizes nucleosomes and regulates gene expression and epigenetic reprogramming. RTs are broadly classified into cranial (atypical teratoid RTs / ATRTs) and extra-cranial RTs (malignant RTs / MRTs), yet the extent to which they are different or similar was not fully determined. Previous reports indicated some shared molecular features between the two entities, but there had been no direct comparison between ATRTs and MRTs. Furthermore, previous reports indicated clinical and histological heterogeneity within and across ATRTs and MRTs, yet the extent of molecular heterogeneity was unknown, particularly in MRTs for which genomic, transcriptomic and epigenomic data were lacking. To address these knowledge gaps, I hypothesized that multi-omic data analyses would identify novel mutations, and gene expression and epigenetic features in MRTs and that such analyses could identify potential molecular underpinnings of heterogeneity. To test these hypotheses, I analyzed whole genome, transcriptome, DNA methylome, histone H3K27me3 and H3K27ac modification profiles obtained from 40 MRT cases, and analyzed multi-omics datasets derived from 140 MRT and 161 ATRT cases. My whole genome analyses revealed recurrently altered genes that were previously undescribed in MRTs. Integration of gene expression and epigenetic data revealed the convergence in dysregulation of HOX genes, imprinted genes and other development-regulating genes such as those involved in neural crest development, indicating dysregulation of early human developmental processes in MRTs. I also identified five DNA methylation subgroups of RTs across different anatomical sites. Among these, subgroups containing MRTs and ATRTs expressing relatively high levels of MYC exhibited gene expression signatures and epigenetic modifications indicative of increased immunological activities. I analyzed immunohistochemistry data to confirm increased levels of immune cell infiltration and expression of immune checkpoint proteins in these subgroups. My findings implied the potential utility of immune checkpoint blockade treatments for RT patients despite the low prevalence of mutations in these cancers. Supplementary materials available at: http://hdl.handle.net/2429/77293.

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