Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles
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Date
2025
Authors
Flynn, A.
Pattison, A.D.
Balachander, S.
Boehm, E.
Bowen, B.
Dwight, T.
Rossello, F.J.
Hofmann, O.
Martelotto, L.
Zethoven, M.
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Journal article
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Nature Communications, 2025; 16(1):2632-1-2632-20
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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
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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.
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© The Author(s) 2025. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.