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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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57595-y |
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| author | 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 |
| author_facet | 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 |
| author_sort | Aidan Flynn |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1255e7aad4c7416ca828fa70da730326 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1255e7aad4c7416ca828fa70da7303262025-08-20T03:41:42ZengNature PortfolioNature Communications2041-17232025-03-0116112010.1038/s41467-025-57595-yMulti-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profilesAidan Flynn0Andrew D. Pattison1Shiva Balachander2Emma Boehm3Blake Bowen4Trisha Dwight5Fernando J. Rossello6Oliver Hofmann7Luciano Martelotto8Maia Zethoven9Lawrence S. Kirschner10Tobias Else11Lauren Fishbein12Anthony J. Gill13Arthur S. Tischler14Thomas Giordano15Tamara Prodanov16Jane R. Noble17Roger R. Reddel18Alison H. Trainer19Hans Kumar Ghayee20Isabelle Bourdeau21Marianne Elston22Diana Ishak23Joanne Ngeow Yuen Yie24Rodney J. Hicks25Joakim Crona26Tobias Åkerström27Peter Stålberg28Patricia Dahia29Sean Grimmond30Roderick Clifton-Bligh31Karel Pacak32Richard W. Tothill33Centre for Cancer Research and Department of Clinical Pathology, University of MelbourneCentre for Cancer Research and Department of Clinical Pathology, University of MelbourneCentre for Cancer Research and Department of Clinical Pathology, University of MelbourneCentre for Cancer Research and Department of Clinical Pathology, University of MelbourneCentre for Cancer Research and Department of Clinical Pathology, University of MelbourneKolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSWCentre for Cancer Research and Department of Clinical Pathology, University of MelbourneCentre for Cancer Research and Department of Clinical Pathology, University of MelbourneCentre for Cancer Research and Department of Clinical Pathology, University of MelbournePeter MacCallum Cancer CentreDivision of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State UniversityUniversity of MichiganDepartment of Medicine, Division of Endocrinology, Metabolism, Diabetes, University of ColoradoSydney Medical School, University of SydneyTufts Medical CenterUniversity of MichiganEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentChildren’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyChildren’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyPeter MacCallum Cancer CentreUniversity of Florida and Malcom Randall VA Medical CenterDivision of endocrinology and Research Center, Center hospitalier de l’Université de MontréalWaikato Clinical Campus, University of AucklandCancer Genetics Service, National Cancer Center SingaporeCancer Genetics Service, National Cancer Center SingaporeSt Vincent’s Dept of Medicine, University of MelbourneDepartment of Medical Sciences, Uppsala UniversityDepartment of Surgical Sciences, Uppsala UniversityDepartment of Surgical Sciences, Uppsala UniversityDiv. Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio (UTHSCSA)Centre for Cancer Research and Department of Clinical Pathology, University of MelbourneKolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSWEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentCentre for Cancer Research and Department of Clinical Pathology, University of MelbourneAbstract 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.https://doi.org/10.1038/s41467-025-57595-y |
| spellingShingle | 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 Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles Nature Communications |
| title | Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles |
| title_full | Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles |
| title_fullStr | Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles |
| title_full_unstemmed | Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles |
| title_short | Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles |
| title_sort | multi omic analysis of sdhb deficient pheochromocytomas and paragangliomas identifies metastasis and treatment related molecular profiles |
| url | https://doi.org/10.1038/s41467-025-57595-y |
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