Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

SIMPLE SUMMARY: Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that are often hereditary. Although research has advanced considerably, significant gaps still persist in understanding risk factors, predicting metastatic potential and treating aggressive tumors. The study of rare mutations can provide new insights into how pheochromocytomas and paragangliomas develop. In this review, we provide examples of such rare events and how they can inform our understanding of the spectrum of mutations that can lead to these tumors and improve our ability to provide a genetic diagnosis. ABSTRACT: Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in cancer. In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior.