"Interrogating the genomic and metabolomic landscape of pseudohypoxic phaeochromocytoma and paraganglioma syndromes"

Phaeochromocytomas and paragangliomas (PPGLs) are rare neural-crest derived tumours with one of the highest germline heritability rates of all neoplasias at ~40%[1, 2]. Molecular genetic testing and transcriptional stratification of PPGLs have highlighted that tumours with succinate dehydrogenase deficiency (SDHx) are among the most frequently mutated group of susceptibility genes. Identifying individuals carrying a pathogenic variant in one of these genes leads to lifelong surveillance. Despite the low tumour penetrance, SDHx deficient PPGLs are associated with an aggressive disease course, with a 5-year overall survival of 50% in individuals with metastatic disease[3]. Predicting the development of a primary tumour or progression to metastatic disease throughout the life course with imaging/plasma metanephrines and histopathological scoring systems has limitations[4, 5]. The discovery of metabolic rewiring of SDHx deficiency at the tumour level holds promise as a non-invasive disease biomarker. Endothelial PAS domain protein 1 (EPAS1 or HIF2A) is another pseudohypoxia-associated gene that is rarely identified in sporadic PPGLs and, in the postzygotic somatic mosaic state, leads to the development of Pacak-Zhuang syndrome, associated with a high metastatic rate[6]. There is a critical need to develop pseudohypoxic murine models to elucidate the molecular mechanisms of tumourigenesis and investigate novel therapeutics further. To date, a SDHx deficient murine model recapitulating tumour development has not been developed, and non-cancerous phenotypes have only been described in the Epas1 murine model, thus we sought out to develop and validate the adrenal phenotypes of these two PPGL syndromes in murine models[7]. This bench-to-bedside approach has 1) explored metabolic biomarkers in SDHx deficiency and 2) utilised two pseudohypoxic murine models. These approaches have identified plasma metabolites with clinical utility for those with SDHx deficiency, provided new insights into the role pseudohypoxia-associated genes have in adrenal development, and brought two models of phaeochromocytoma tumourlet models.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Cole, Yasemin

Advisors dc:contributor.advisor

• Maher, Eamonn
• Casey, Ruth

• hypoxia
• paraganglioma
• phaeochromocytoma
• SDHx

Licence

• https://www.repository.cam.ac.uk/bitstreams/1a7d83e5-44b4-4ae6-a992-b66c5339e849/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.120728

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/388330