Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Bioinformatics Unit, Structural Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Nat Commun. 2023 Feb 28;14(1):1122. doi: 10.1038/s41467-023-36769-6.
The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.
导致嗜铬细胞瘤/副神经节瘤转移的机制尚不清楚，这阻碍了转移性肿瘤（mPPGL）患者的治疗选择。在此，我们通过对一大群 mPPGL 进行基因组分析表明，高突变负荷、微卫星不稳定性和体细胞拷贝数改变负担与 ATRX/TERT 改变相关，是合适的预后标志物。转录组分析定义了获得转移能力所涉及的信号网络，并建立了与 mPPGL 相关的基因特征，突出了 CDK1 作为另一个 mPPGL 标志物。免疫基因组学伴随免疫组化鉴定了肿瘤微环境水平上的异质生态系统，与基因组亚型和肿瘤行为相关。具体来说，我们定义了 mPPGL 中普遍存在的免疫抑制微环境，PD-L1 表达的 MAML3 相关肿瘤除外。我们的研究揭示了转移风险的典型标志物，并表明在 PPGL 预后和识别可能受益于免疫治疗的患者的临床管理中纳入免疫参数是有用的。
