Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles.
Richard William TothillAidan FlynnAndrew PattisonShiva BalachanderEmma BoehmBlake BowenTrisha DwightFernando RosselloOliver HofmannLuciano G MartelottoMagnus ZethovenLawrence KirschnerTobias ElseLauren FishbeinAnthony GillArthur TischlerThomas GiordanoJane NobleTamara ProdanovRoger R ReddelAlison TrainerHans GhayeeIsabelle BourdeauMarianne ElstonNur Diana Binte IshakJoanne Ngeow Yuen YieRodney HicksJoakim CronaTobias ÅkerströmPeter StålbergPatricia L M DahiaSean M GrimmondRoderick John Clifton-BlighKarel PacakPublished in: Research square (2024)
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 performed multi-omic analysis on 94 tumours from 79 patients using seven molecular methods. Sympathetic (chromaffin cell) and parasympathetic (non-chromaffin cell) PCPG had distinct molecular profiles reflecting their cell-of-origin and biochemical profile. TERT and ATRX-alterations were associated with metastatic PCPG and these tumours had an increased mutation load, and distinct transcriptional and telomeric features. Most PCPG had quiet genomes with some rare co-operative driver events observed, including EPAS1/HIF-2α mutations. Two mechanisms of acquired resistance to DNA alkylating chemotherapies were also detected - MGMT overexpression and mismatch repair-deficiency causing hypermutation. Our comprehensive multi-omic analysis of SDHB-mutant PCPG therefore identified features of metastatic disease and treatment response, expanding our understanding of these rare neuroendocrine tumours.
Keyphrases
- single cell
- squamous cell carcinoma
- cell therapy
- small cell lung cancer
- end stage renal disease
- transcription factor
- gene expression
- ejection fraction
- chronic kidney disease
- prognostic factors
- stem cells
- genome wide
- cell proliferation
- circulating tumor
- endothelial cells
- dna methylation
- peritoneal dialysis
- mesenchymal stem cells
- dna damage
- patient reported outcomes
- stress induced
- heart rate
- dna damage response