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A study of succinate dehydrogenase deficient tumourigenesis: From functional assessment of variant pathogenicity to the discovery of new disease biomarkers 10.17863/CAM.39029 Casey, Ruth Maher, Eamonn A loss of function of the citric acid cycle enzyme complex succinate dehydrogenase (SDH) is associated with a predisposition to a spectrum of tumourigenesis including phaeochromocytoma, paraganglioma (1) (PPGL), gastrointestinal stromal tumours (GIST) (2), renal cell carcinoma (RCC) (3) and pituitary adenomas (4). Pathogenic variants in each of the four genes (SDHx) encoding the four sub-components of this complex (SDHA/B/C/D) have been associated with tumourigenesis. Germline pathogenic variants in SDHB account for up to 50% of patients with malignant PPGL and a 5 year survival of less than 50% in those with malignancy (5). Most SDHx variant carriers require life long surveillance for tumour development (6) but predicting malignant disease is challenging and histology is of limited assistance in this prediction. The advent of next generation sequencing (NGS) has been influential in this field of inherited neoplasia allowing more rapid and accurate identification of pathogenic variants in the SDHx genes. However the increased throughput achieved with NGS methodology has yielded more variants of uncertain significance in these genes which require additional assessment. New diagnostic adjuncts such as SDHB immunohistochemistry(7), have provided additional prognostic information and prediction of malignant risk but further biomarkers are needed. Furthermore there is a lack of effective treatments for malignant disease associated with SDHx variants (8) (9). This ‘multi-omics’ investigation has provided new insights into genotype-phenotype correlations in SDH deficient disease and has facilitated the translation of new techniques into clinical utility which will aid SDHx variant interpretation. This study has evaluated novel disease biomarkers and potential therapeutic targets in SDH deficient tumour University of Cambridge 2019-07-20 Thesis Doctoral Doctor of Philosophy (PhD) en Health Research Board Ireland, GIST support UK https://www.repository.cam.ac.uk/handle/1810/291871 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/b63eaeb0-67a9-4684-ae07-24b324b8d940/download 689c0b41255b2c9a4a5488d52dcd31e7 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f3174a54-148b-4335-9f43-daaacd5cc914/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Phaeochromocytoma paraganglioma Succinate dehydrogenase metabolomics GIST