蛋白质组学很少用于鉴定异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤（GB）的新型预后和/或治疗标记物。在本研究中，我们通过基于数据独立采集质谱 (DIA-MS) 的蛋白质组学分析了 IDH 野生型 GB 短期和长期幸存者（分别为 STS 和 LTS）的 50 个肿瘤样本和 30 个血清样本，其中识别此类标记的目的。 DIA-MS 在肿瘤和血清样本中分别鉴定了 5422 个和 826 个标准化蛋白，其中只有 3 个肿瘤蛋白和 26 个血清蛋白在 STS 和 LTS 组之间表现出显着差异表达。这些失调的蛋白质主要与活性氧（ROS）的解毒有关。特别是，STS组中的GB患者血清中苹果酸脱氢酶1（MDH1）和核糖核酸酶抑制剂1（RNH1）水平较高，而脂肪酸结合蛋白7（FABP7）肿瘤水平较低，这可能使他们能够维持低水平。 ROS 水平，抵消放疗加伴随和辅助替莫唑胺一线治疗的效果。根据 96 名 IDH 野生型 GB 患者的血清蛋白质组数据，基于 MDH1 和 RNH1 表达水平的血液评分被发现是生存的独立预后因素。本研究强调了循环 MDH1 和 RNH1 生物标志物在确定 IDH 野生型 GB 患者预后方面的效用。此外，这些生物标志物驱动的通路以及肿瘤 FABP7 通路可能构成阻断 ROS 解毒的有前途的治疗靶点，以克服潜在 GB STS 中对放化疗的耐药性。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Proteomics has been little used for the identification of novel prognostic and/or therapeutic markers in isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GB). In this study, we analyzed 50 tumor and 30 serum samples from short- and long-term survivors of IDH-wildtype GB (STS and LTS, respectively) by data-independent acquisition mass spectrometry (DIA-MS)-based proteomics, with the aim of identifying such markers. DIA-MS identified 5422 and 826 normalized proteins in tumor and serum samples, respectively, with only three tumor proteins and 26 serum proteins displaying significant differential expression between the STS and LTS groups. These dysregulated proteins were principally associated with the detoxification of reactive oxygen species (ROS). In particular, GB patients in the STS group had high serum levels of malate dehydrogenase 1 (MDH1) and ribonuclease inhibitor 1 (RNH1) and low tumor levels of fatty acid-binding protein 7 (FABP7), which may have enabled them to maintain low ROS levels, counteracting the effects of the first-line treatment with radiotherapy plus concomitant and adjuvant temozolomide. A blood score built on the levels of MDH1 and RNH1 expression was found to be an independent prognostic factor for survival based on the serum proteome data for a cohort of 96 IDH-wildtype GB patients. This study highlights the utility of circulating MDH1 and RNH1 biomarkers for determining the prognosis of patients with IDH-wildtype GB. Furthermore, the pathways driven by these biomarkers, and the tumor FABP7 pathway, may constitute promising therapeutic targets for blocking ROS detoxification to overcome resistance to chemoradiotherapy in potential GB STS.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.