Genetic and epigenetic characterisation of phaeochromocytoma and paraganglioma tumours

Student thesis: Doctoral ThesisDoctor of Philosophy


Phaeochromocytomas and paragangliomas (PPGLs) are neuroendocrine tu-mours that affect the adrenal glands and paraganglia of the sympathetic and parasympathetic chain respectively. They frequently cause catecholamine excess which can induce life-threatening complications. Patients with this genetically-driven cancer, especially with metastatic disease, currently have limited therapeutic options. Although the approximately 20 genes that are responsible for 40% of cases, and are implicated in 60% of the tumours, are known, their precise effects on the epigenome are not fully understood. This is crucial because a subset of tumours with mutations in the implicated genes exhibit accumulation of oncometabolites that inhibit DNA and histone demethylation.
The first part of this thesis characterises the DNA methylation profiles of 50 such tumours, both familial and sporadic, using high resolution Illumina MethylationEPIC arrays. We show that SDHB tumours, which have the highest rates of malignancy, also have the highest levels of DNA methylation. Enrichment analysis of the differentially methylated loci identified over-representation of important pathways including of extra-cellular matrix organisation and receptor tyrosine kinase signaling. Where clinical data are available, correlates with important corresponding characteristics are made to identify the transcriptional reprogramming of metastatic disease. Methylation of the PACSIN3 promoter was linked to aggressive SDHB tumours while 23 probes were associated with metastatic disease in SDHB patients. The transcriptomes of 28 of those samples are also described, allowing the study of the effects of DNA methylation on gene expression, which was only moderate, even in the case of differentially methylated promoters of Cluster 1A tumours. Enrichment analysis revealed significant overlap with over-represented pathways from the DNA methylation data. Such convergence could indicate that irrespective of the causal PPGL gene mutation, a common subset of essential pathways tends to be perturbed.
Finally, germline and tumour exomes of two patients with constitutional mutations are described in detail in order to understand their role in tumouri-genesis. The first patient presented with multiple tumours and concurrent germline mutations in two predisposing genes (NF1 and SDHD) of different aetiologic mechanisms. Molecular analysis of the tumour, including DNA methylation and immunohistochemistry data, revealed that the it is consistent with SDHD-related disease. The second case had a variant of unknown significance in a predisposing gene (RET ) and two different neuroendocrine tumours; a phaeochromocytoma and a thyroid carcinoma. Germline and so-matic sequencing did not reveal any obvious causal variants suggesting that the RET variant could be pathogenic and responsible for both tumours.
Date of Award1 Aug 2021
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorRebecca Oakey (Supervisor) & Louise Izatt (Supervisor)

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