Heather Wachtel1, Lauren Fishbein2. 1. Hospital of the University of Pennsylvania, Department of Surgery, Division of Endocrine and Oncologic Surgery and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 2. University of Colorado School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism and Diabetes and the Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, Colorado, USA.
Abstract
PURPOSE OF REVIEW: This review summarizes our current understanding of germline and somatic genetics and genomics of pheochromocytomas and paragangliomas (PCC/PGL), describes existing knowledge gaps, and discusses future research directions. RECENT FINDINGS: Germline pathogenic variants (PVs) are found in up to 40% of those with PCC/PGL. Tumors with germline PVs are broadly categorized as Cluster 1 (pseudohypoxia), including those with SDH, VHL, FH, and EPAS1 PVs, or Cluster 2 (kinase signaling) including those with NF1, RET, TMEM127, and MAX PVs. Somatic driver mutations exist in some of the same genes (RET, VHL, NF1, EPAS1) as well as in additional genes including HRAS, CSDE1 and genes involved in cell immortalization (ATRX and TERT). Other somatic driver events include recurrent fusion genes involving MAML3. SUMMARY: PCC/PGL have the highest association with germline PVs of all human solid tumors. Expanding our understanding of the molecular pathogenesis of PCC/PGL is essential to advancements in diagnosis and surveillance and the development of novel therapies for these unique tumors.
PURPOSE OF REVIEW: This review summarizes our current understanding of germline and somatic genetics and genomics of pheochromocytomas and paragangliomas (PCC/PGL), describes existing knowledge gaps, and discusses future research directions. RECENT FINDINGS: Germline pathogenic variants (PVs) are found in up to 40% of those with PCC/PGL. Tumors with germline PVs are broadly categorized as Cluster 1 (pseudohypoxia), including those with SDH, VHL, FH, and EPAS1 PVs, or Cluster 2 (kinase signaling) including those with NF1, RET, TMEM127, and MAX PVs. Somatic driver mutations exist in some of the same genes (RET, VHL, NF1, EPAS1) as well as in additional genes including HRAS, CSDE1 and genes involved in cell immortalization (ATRX and TERT). Other somatic driver events include recurrent fusion genes involving MAML3. SUMMARY:PCC/PGL have the highest association with germline PVs of all human solid tumors. Expanding our understanding of the molecular pathogenesis of PCC/PGL is essential to advancements in diagnosis and surveillance and the development of novel therapies for these unique tumors.
Authors: N Tufton; R J Hearnden; D M Berney; W M Drake; L Parvanta; J P Chapple; S A Akker Journal: Endocr Relat Cancer Date: 2022-09-19 Impact factor: 5.900