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

Flynn, A; Pattison, AD; Balachander, S; Boehm, E; Bowen, B; Dwight, T; Rossello, FJ; Hofmann, O; Martelotto, L; Zethoven, M; Kirschner, LS; Else, T; Fishbein, L; Gill, AJ; Tischler, AS; Giordano, T; Prodanov, T; Noble, JR; Reddel, RR; Trainer, AH; Ghayee, HK; Bourdeau, I; Elston, M; Ishak, D; Ngeow Yuen Yie, J; Hicks, RJ; Crona, J; &#197;kerstr&#246;m, T; St&#229;lberg, P; Dahia, P; Grimmond, S; Clifton-Bligh, R; Pacak, K; Tothill, RW

Author(s): Flynn, A; Pattison, AD; Balachander, S; Boehm, E; Bowen, B; Dwight, T; Rossello, FJ; Hofmann, O; Martelotto, L; Zethoven, M; Kirschner, LS; Else, T; Fishbein, L; Gill, AJ; Tischler, AS; Giordano, T; Prodanov, T; Noble, JR; Reddel, RR; Trainer, AH; Ghayee, HK; Bourdeau, I; Elston, M; Ishak, D; Ngeow Yuen Yie, J; Hicks, RJ; Crona, J; Åkerström, T; Stålberg, P; Dahia, P; Grimmond, S; Clifton-Bligh, R; Pacak, K; Tothill, RW;
Details: Publication Year 2025-03-17,Volume 16,Issue #1,Page 2632
Journal Title: Nature Communications
Publication Type: Research article
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.
Publisher: Springer Nature
Keywords: Humans; *Pheochromocytoma/genetics/pathology; *Paraganglioma/genetics/pathology; *Succinate Dehydrogenase/genetics/deficiency/metabolism; *Adrenal Gland Neoplasms/genetics/pathology; Female; Male; Adult; Neoplasm Metastasis; Middle Aged; Mutation; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism; X-linked Nuclear Protein/genetics/metabolism; Tumor Suppressor Proteins/genetics/metabolism; DNA Repair Enzymes/genetics/metabolism; Young Adult; Aged; Adolescent; Biomarkers, Tumor/genetics/metabolism; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm/genetics; Multiomics; DNA Modification Methylases
Department(s): Laboratory Research; Ambulatory Services
Publisher's Version: https://doi.org/10.1038/s41467-025-57595-y
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-57595-y
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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