| Title: |
Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles |
| Authors: |
Flynn, Aidan; Pattison, Andrew David; Balachander, Shiva; Boehm, Emma; Bowen, Blake; Dwight, Trisha; Rossello, F. J.; Hofmann, Oliver M.; Martelotto, Luciano G.; Zethoven, Magnus; Kirschner, Lawrence S.; Else, Tobias; Fishbein, Lauren; Gill, Anthony J.; Tischler, Arthur S.; Giordano, Thomas J.; Prodanov, Tamara; Noble, Jane R.; Reddel, Roger R.; Trainer, Alison H.; Ghayee, Hans Kumar; Bourdeau, Isabelle; Elston, Marianne S.; Ishak, Diana; Ngeow Yuen Yie, Joanne; Hicks, Rodney J.; Crona, Joakim; Åkerström, Tobias; Stal̊berg, Peter L.H.; Dahia, Patricia; Grimmond, Sean M.; Clifton-Bligh, Roderick J.; Pacak, Karel; Tothill, Richard William |
| Contributors: |
Lee Kong Chian School of Medicine (LKCMedicine) |
| Publication Year: |
2025 |
| Collection: |
DR-NTU (Digital Repository at Nanyang Technological University, Singapore) |
| Subject Terms: |
Medicine; Health and Life Sciences |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Nature Communications; https://hdl.handle.net/10356/209491; 16; 2632 |
| DOI: |
10.1038/s41467-025-57595-y |
| Availability: |
https://hdl.handle.net/10356/209491; https://doi.org/10.1038/s41467-025-57595-y |
| Rights: |
© 2025 Nature Research. All rights reserved. |
| Accession Number: |
edsbas.8A0EFCA2 |
| Database: |
BASE |