Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles

Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles

Abstract Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we perform multi-omic a...

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Main Authors: Aidan Flynn, Andrew D. Pattison, Shiva Balachander, Emma Boehm, Blake Bowen, Trisha Dwight, Fernando J. Rossello, Oliver Hofmann, Luciano Martelotto, Maia Zethoven, Lawrence S. Kirschner, Tobias Else, Lauren Fishbein, Anthony J. Gill, Arthur S. Tischler, Thomas Giordano, Tamara Prodanov, Jane R. Noble, Roger R. Reddel, Alison H. Trainer, Hans Kumar Ghayee, Isabelle Bourdeau, Marianne Elston, Diana Ishak, Joanne Ngeow Yuen Yie, Rodney J. Hicks, Joakim Crona, Tobias Åkerström, Peter Stålberg, Patricia Dahia, Sean Grimmond, Roderick Clifton-Bligh, Karel Pacak, Richard W. Tothill
Format: Article
Language:English
Published: Nature Portfolio 2025-03-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-57595-y
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Summary:Abstract Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we perform multi-omic analysis on 94 tumours from 79 patients using seven molecular methods. Sympathetic (chromaffin cell) and parasympathetic (non-chromaffin cell) PCPG have distinct molecular profiles reflecting their cell-of-origin and biochemical profile. TERT and ATRX-alterations are associated with metastatic PCPG and these tumours have an increased mutation load, and distinct transcriptional and telomeric features. Most PCPG have quiet genomes with some rare co-operative driver events, including EPAS1/HIF-2α mutations. Two mechanisms of acquired resistance to DNA alkylating chemotherapies are identifiable; MGMT overexpression and mismatch repair-deficiency causing hypermutation. Our comprehensive multi-omic analysis of SDHB-mutant PCPG therefore identifies features of metastatic disease and treatment response, expanding our understanding of these rare neuroendocrine tumours.
ISSN:2041-1723

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