【文献分享】Multi-omic analysis of SDHB-deficient提供了数据和代码

介绍

遗传性 SDHB 突变嗜铬细胞瘤 (PC) 和副神经节瘤 (PG) 是罕见的肿瘤，尽管其临床行为不可预测，但具有很高的转移倾向。为了表征这些肿瘤的基因组景观并识别转移生物标志物，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) PCPG 具有不同的分子谱，反映了它们的细胞来源和生化谱。TERT 和 ATRX 改变与转移性 PCPG 有关，这些肿瘤具有增加的突变负荷以及不同的转录和端粒特征。大多数 PCPG 具有安静的基因组，具有一些罕见的协同驱动事件，包括 EPAS1/HIF-2α 突变。可以识别出两种对 DNA 烷基化化疗获得性耐药的机制； MGMT 过度表达和错配修复缺陷导致超突变。因此，我们对 SDHB 突变型 PCPG 的全面多组学分析确定了转移性疾病和治疗反应的特征，扩大了我们对这些罕见神经内分泌肿瘤的了解。

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.

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代码

• https://github.com/UMCCR-RADIO-Lab/a5_sdhb_pcpg/tree/main