Metastatic progression of pheochromocytoma and paraganglioma occurs via parallel evolution

Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and ganglia of the autonomic nervous system. Approximately one-third are causatively associated with pathogenic germline variants. Metastatic disease develops in up to 25% of patients with PCC/PGL, for whom therapeutic options are limited, and no targeted treatments exist. Tumor evolution in metastatic PCC/PGL has not been well delineated. We performed whole-exome sequencing of paired specimens from 27 patients with metastatic PCC/PGL to better understand cancer progression. Tumors demonstrate high rates of loss-of-function variants in chromatin remodeling and DNA damage repair genes, suggesting potential therapeutic targets. Low rates of shared somatic variants were observed between primary tumors and metastases, with evidence of independent monoclonal pathogenic variants in metastatic tumors. These findings suggest that PCC/PGL metastases develop via monoclonal seeding and parallel progression.