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<p>Hereditary <i>SDHB</i>-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. <i>TERT</i> and <i>ATRX</i>-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 <i>EPAS1</i>/HIF-2α mutations. Two mechanisms of acquired resistance to DNA alkylating chemotherapies are identifiable; <i>MGMT</i> overexpression and mismatch repair-deficiency causing hypermutation. Our comprehensive multi-omic analysis of <i>SDHB</i>-mutant PCPG therefore identifies features of metastatic disease and treatment response, expanding our understanding of these rare neuroendocrine tumours.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月17日

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  • 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

摘要

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.