Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Neurology and Neurooncology Program at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
J Neurochem. 2021 Jul;158(2):522-538. doi: 10.1111/jnc.15350. Epub 2021 Apr 9.
Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.
近年来，液体活检技术在分子诊断方面取得了进展，有望在无需进行侵入性手术获取组织的情况下，重复监测脑恶性肿瘤的肿瘤演变和治疗反应。在这里，我们实施了一种基于质谱的蛋白质分析方案，该方案在回顾性和前瞻性观察研究中，专注于脑胶质瘤，对四种脑恶性肿瘤（脑胶质瘤、淋巴瘤、脑转移和软脑膜疾病[LMD]）患者的 251 份脑脊液（CSF）样本和健康个体的数百种蛋白质进行了鉴定。通过破坏血脑屏障，CSF 中的蛋白质组失调似乎在脑肿瘤实体中基本保持一致。对脑胶质瘤患者的 CSF 分析确定了两个与肿瘤大小和患者生存相关的蛋白质组学聚类。通过将 CSF 数据与匹配的脑胶质瘤肿瘤组织和原代脑胶质瘤细胞的蛋白质组学分析相结合，我们确定了脑胶质瘤的潜在 CSF 生物标志物，特别是几丁质酶 3 样蛋白 1（CHI3L1）和神经胶质纤维酸性蛋白（GFAP）。这些关键发现在前瞻性队列中的 35 名胶质瘤患者中得到了验证。最后，在经常进行重复 CSF 检查的 LMD 患者中，我们探索了我们的蛋白质组学方案，作为对连续 CSF 样本进行分析的一种手段。因此，脑恶性肿瘤 CSF 的蛋白质组学分析具有揭示诊断和治疗监测生物标志物的潜力。
