Flynn Aidan, Pattison Andrew D, Balachander Shiva, Boehm Emma, Bowen Blake, Dwight Trisha, Rossello Fernando J, Hofmann Oliver, Martelotto Luciano, Zethoven Maia, Kirschner Lawrence S, Else Tobias, Fishbein Lauren, Gill Anthony J, Tischler Arthur S, Giordano Thomas, Prodanov Tamara, Noble Jane R, Reddel Roger R, Trainer Alison H, Ghayee Hans Kumar, Bourdeau Isabelle, Elston Marianne, Ishak Diana, Ngeow Yuen Yie Joanne, Hicks Rodney J, Crona Joakim, Åkerström Tobias, Stålberg Peter, Dahia Patricia, Grimmond Sean, Clifton-Bligh Roderick, Pacak Karel, Tothill Richard W
Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, VIC, Australia.
Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW, Melbourne, Australia.
Nat Commun. 2025 Mar 17;16(1):2632. doi: 10.1038/s41467-025-57595-y.
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.
遗传性SDHB突变型嗜铬细胞瘤（PC）和副神经节瘤（PG）是罕见肿瘤，尽管其临床行为不可预测，但具有较高的转移倾向。为了描述这些肿瘤的基因组特征并鉴定转移生物标志物，我们使用七种分子方法对来自79名患者的94个肿瘤进行了多组学分析。交感神经（嗜铬细胞）和副交感神经（非嗜铬细胞）来源的PCPG具有不同的分子特征，反映了它们的起源细胞和生化特征。TERT和ATRX改变与转移性PCPG相关，这些肿瘤的突变负荷增加，具有独特的转录和端粒特征。大多数PCPG的基因组较为稳定，存在一些罕见的协同驱动事件，包括EPAS1/HIF-2α突变。可识别出两种对DNA烷化化疗获得性耐药的机制；MGMT过表达和错配修复缺陷导致高突变。因此，我们对SDHB突变型PCPG进行的全面多组学分析确定了转移性疾病和治疗反应的特征，扩展了我们对这些罕见神经内分泌肿瘤的认识。
