Genetic profiling of phaeochromocytoma and paraganglioma: towards precision medicine

Abstract

Phaeochromoctyoma and paraganglioma (PC/PGL) are rare neuroendocrine tumours of neural crest origin, arising within the adrenal medulla and sympathetic/parasympathetic chain. High heritability is a unique feature of PC/PGL with up to 30% of tumours developing in the context of an underling germline pathogenic variant. Germline pathogenic variants occur broadly within two clusters: Cluster 1 characterised by pseudohypoxia and culminating in hypoxia-inducible factor stabilisation, and Cluster 2 which involves kinase signalling pathways. Genotype-phenotype correlations are well recognised for syndromes associated with Von Hippel Lindau disease (VHL), Multiple Endocrine Neoplasia Type 2 syndrome (RET) and Familial Paraganglioma Syndrome Types 1 and 4 (SDHD and SDHB, respectively). Many additional hereditary genes have been discovered are routinely tested in patients presenting with PC/PGL, including FH, MAX, SDHA, SDHAF2, SDHC and TMEM127.

This thesis described contemporary methods for streamlining the diagnosis of hereditary causes of PC/PGL (including variant interrogation) and investigation for markers of PC/PGL disease behaviour utilising paired tumour-blood samples for molecular analysis via next-generation-, RNA- and mitochondrial-sequencing. The emerging phenotypes of infrequently described cohorts of patients diagnosed with PC/PGL, due to their rarity, were expanded in Multiple Endocrine Neoplasia type 5 due to germline MAX, Pacak-Zhuang syndrome arising due to post-zygotic somatic mosaicism of EPAS1, and paediatric and adolescent patients diagnosed with PC/PGL. Lastly, the efficacy of peptide receptor radionuclide therapy for the treatment of inoperable and metastatic disease was reported.

Overall, the beneficial role of precision medicine with the genetic profiling of patients diagnosed with PC/PGL was established, allowing the development of personalised care for these individuals.