Genetic drivers, telomere maintenance and metabolism in development of high-risk pheochromocytoma and abdominal paraganglioma

Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) originate from the adrenal medulla or sympathetic paraganglia.

Here we aim to further clarify key events of underlying driver mutations, telomerase activation, aberrant metabolism and genes defining tumor subpopulations in development of malignant behavior and how these can applied in improved clinical work-up.- Assess the calcium channel CACNAH1 as a novel susceptibility gene in PCC and search for and characterize novel driver mutations in PCC/aPGL with malignant features.- Further elucidate telomere stabilising events in development of malignancy in PCC/aPGL and possible co-operation with known risk genes for PCC/aPGL.

Special attention will be payed to when the telomere stabilising alteration took place and if it can precede clinical recognition of malignant behavior.- Determine the extent of aberrant mitochondrial respiration, indicated in previous study, and its possible relation to molecular subgroups and drug repurposing for PCC/aPGL.- Determine relationship between key genetic aberrations and detailed tumor features of patient risk groups in PCC/aPGL focusing on genes defining cell populations in normal adrenal and tumors based on single cell sequencing.The project is proposed to result in improved understanding of tumor development and malignant behavior of PCC/aPGL and provide tools for clinical dilemmas related to early recognition of risk tumors allowing appropriate initial intervention and follow-up.