Guilhamon, PCM; (2014) Epigenomics of Sarcomas. Doctoral thesis , UCL (University College London).

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Abstract

Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukemia (AML), lower-grade glioma (LGG), and cholangiocarcinoma (CC). In these three malignancies, mutant IDH status is associated with increased 2-hydroxyglutarate (2-HG) production and a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here I show that the IDH variants in chondrosarcoma (CS) are also associated with a hypermethylation phenotype, supporting the role of mutant IDH-produced 2-HG as an inhibitor of TET-mediated DNA demethylation. The associated gene expression profile is also investigated, highlighting the need for a better understanding of DNA methylation-mediated transcriptional regulation. The generated methylation data is additionally harnessed to reveal novel copy number variants in CS. Meta-analysis of the AML, LGG, CC and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, I identify the transcription factor EBF1 as an interaction partner for TET2, in the first description of a targeted demethylation pathway. In an effort to assess whether patient-derived tumour xenografts (PDXs) are suitable models for epigenetic research in rare and common cancers, such as osteosarcoma (OS) and colon cancer, respectively, I compare PDXs to their matched patient tumour and reveal that an average of only 2.7% of the assayed methylome undergoes major methylation changes with xenografting. In addition, no further changes are identified in subsequent PDX generations, making these models highly suitable for expansion of rare tumours and preclinical drug screening. Finally I propose a model to inform future study design and statistically dilute those methylation shifts identified in PDXs.

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