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

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 () and Richard W. Tothill ()
Additional contact information
Aidan Flynn: University of Melbourne
Andrew D. Pattison: University of Melbourne
Shiva Balachander: University of Melbourne
Emma Boehm: University of Melbourne
Blake Bowen: University of Melbourne
Trisha Dwight: Royal North Shore Hospital St Leonards NSW
Fernando J. Rossello: University of Melbourne
Oliver Hofmann: University of Melbourne
Luciano Martelotto: University of Melbourne
Maia Zethoven: Peter MacCallum Cancer Centre
Lawrence S. Kirschner: The Ohio State University
Tobias Else: University of Michigan
Lauren Fishbein: University of Colorado
Anthony J. Gill: University of Sydney
Arthur S. Tischler: Tufts Medical Center
Thomas Giordano: University of Michigan
Tamara Prodanov: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Jane R. Noble: The University of Sydney
Roger R. Reddel: The University of Sydney
Alison H. Trainer: Peter MacCallum Cancer Centre
Hans Kumar Ghayee: University of Florida and Malcom Randall VA Medical Center
Isabelle Bourdeau: Center hospitalier de l’Université de Montréal
Marianne Elston: University of Auckland
Diana Ishak: National Cancer Center Singapore
Joanne Ngeow Yuen Yie: National Cancer Center Singapore
Rodney J. Hicks: University of Melbourne
Joakim Crona: Uppsala University
Tobias Åkerström: Uppsala University
Peter Stålberg: Uppsala University
Patricia Dahia: University of Texas Health Science Center at San Antonio (UTHSCSA)
Sean Grimmond: University of Melbourne
Roderick Clifton-Bligh: Royal North Shore Hospital St Leonards NSW
Karel Pacak: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Richard W. Tothill: University of Melbourne

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57595-y

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