Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles
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.
Authors
- Aidan Flynn (ORCID: https://orcid.org/0000-0002-1933-505X)
- Tobias Else (ORCID: https://orcid.org/0000-0002-2262-0011)
- Fernando J. Rossello (ORCID: https://orcid.org/0000-0003-3885-8777)
- Arthur S. Tischler (ORCID: https://orcid.org/0000-0002-9726-5739)
- Joakim Crona (ORCID: https://orcid.org/0000-0003-0677-4894)
- Roger R. Reddel (ORCID: https://orcid.org/0000-0002-6302-6107)
- Luciano G. Martelotto (ORCID: https://orcid.org/0000-0002-9625-1183)
- Andrew Pattison (ORCID: https://orcid.org/0000-0001-9417-7461)
- Tamara Prodanov (ORCID: https://orcid.org/0009-0007-3887-5303)
- Anthony James Gill (ORCID: https://orcid.org/0000-0002-9447-1967)
- Marianne S. Elston (ORCID: https://orcid.org/0000-0002-0748-2300)
- Lawrence Steven Kirschner (ORCID: https://orcid.org/0000-0001-6180-342X)
- Sean M. Grimmond (ORCID: https://orcid.org/0000-0002-8102-7998)
- Emma Boehm (ORCID: https://orcid.org/0000-0001-7631-9147)
- Trisha Dwight (ORCID: https://orcid.org/0000-0003-1943-4514)
- Lauren Fishbein (ORCID: https://orcid.org/0000-0002-8151-5107)
- Blake Bowen
- Rodney J. Hicks (ORCID: https://orcid.org/0000-0002-0758-0824)
- Shiva Balachander (ORCID: https://orcid.org/0000-0002-4765-6352)
- Diana Ishak
- Roderick John Clifton-Bligh (ORCID: https://orcid.org/0000-0002-1545-0368)
- Karel Pacák (ORCID: https://orcid.org/0000-0002-3541-3767)
- Thomas J. Giordano (ORCID: https://orcid.org/0000-0003-0641-8873)
- Jane R. Noble
- Oliver Hofmann (ORCID: https://orcid.org/0000-0002-7738-1513)
- Joanne Ngeow (ORCID: https://orcid.org/0000-0003-1558-3627)
- Isabelle Bourdeau (ORCID: https://orcid.org/0000-0002-8000-4313)
- Hans K. Ghayee (ORCID: https://orcid.org/0000-0001-9201-3033)
- Richard W. Tothill (ORCID: https://orcid.org/0000-0003-4522-1184)
- Patricia L. M. Dahia (ORCID: https://orcid.org/0000-0002-7757-370X)
- Peter L. H. Stalberg (ORCID: https://orcid.org/0000-0002-9625-1394)
- Tobias Åkerström (ORCID: https://orcid.org/0000-0002-5562-6081)
- Alison H. Trainer
- Maia Zethoven (ORCID: https://orcid.org/0000-0002-6528-891X)
Institutions
- Uppsala University (SE)
- Tufts Medical Center (US)
- The University of Sydney (AU)
- Royal Children's Hospital (AU)
- Children's Medical Research Institute (AU)
- University of Auckland (NZ)
- The University of Melbourne (AU)
- The University of Texas at San Antonio Health Science Center (US)
- Nanyang Technological University (SG)
- University of Michigan (US)
- Royal North Shore Hospital (AU)
- Peter MacCallum Cancer Centre (AU)
- Australian Regenerative Medicine Institute (AU)
- University of Florida (US)
- Victorian Comprehensive Cancer Centre (AU)
- Malcom Randall VA Medical Center (US)
- National Cancer Centre Singapore (SG)
- Centre Hospitalier de l’Université de Montréal (CA)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- Murdoch Children's Research Institute (AU)
- University of Colorado Anschutz Medical Campus (US)
- The Ohio State University (US)
- Monash University (AU)
- University of Colorado Denver (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1038/s41467-025-57595-y
- Citations
- 16
- Primary Topic
- Adrenal and Paraganglionic Tumors
- Type
- article
- Field-Weighted Citation Impact
- 28.09
Funders
- Victorian Cancer Agency
- National Health and Medical Research Council
- National Institute of General Medical Sciences
- Division of Cancer Epidemiology and Genetics, National Cancer Institute