Urinary 8-hydroxy-2’-deoxyguanosine Levels are Elevated in Patients With IDH1-wildtype Glioblastoma and are Associated With Tumor Recurrence in Gliomas

Glial tumors also known as gliomas, are the most widespread form of central nervous system (CNS) neoplasm [1], [2]. In accordance with data and statistics from the American Brain Tumor Association for 2017, glial tumors account for 74.6% of all malignant brain tumors. In the World Health Organization (WHO) report published in 2016, the categorization of CNS tumors according to both histological and molecular characteristics was explained [3], [4]. In this report, isocitrate dehydrogenase (IDH) mutations have been included in the diagnosis criteria of glioma. In 2021, the WHO classification of CNS tumors scheme was also updated. There are major changes in the WHO CNS-5 report that highlight the part of molecular diagnostics in classifying [5]. In the new classification, diffuse glial tumors in adults divided into molecular subtypes based on their status of 1p/19q codeletion and IDH-mutation: IDH-wildtype glial tumor (GBM, Glioblastoma IDH-wildtype), IDH-mutant glial tumor with 1p/19q codeletion and IDH-mutant glial tumor without 1p/19q codeletion (IDH-mutant astrocytoma) [5].

Studies described that mutations in IDH are one of the major events in tumorigenesis in gliomas [6]. There are two isoforms of IDH (IDH1 and IDH2) which can be mutated in gliomas. IDH1 mutation (usually R132H) status has an crucial part in the clinical evaluation of gliomas. Many studies have shown that IDH1 mutant patients have a long-term survival compared to wild-type ones [7], [8].

Oxidative DNA damage has been indicated to play a crucial role in many pathological circumstances, including carcinogenesis. Among the oxidative DNA damage lesions, 8-hydroxy-2'-deoxyguanosine (8-OH-dG), is recognized to be one of the substantial causes of mutagenesis caused by reactive oxygen species [9]. On this basis, 8-OH-dG represents an important biomarker of cellular oxidative stress. Especially, urinary levels of 8-OH-dG reflects the balance between its production and repair in both the nucleotide pool and DNA [9]. Other DNA lesions, (5’S) and (5’R)-8,5’-cyclo-2’-deoxyadenosines (S- and R-cdA) indicate concurrent damage to both base and sugar moieties of the same nucleoside in DNA and may play a crucial part in the development of several diseases [10]. They are formed by hydroxyl radical attack to 2′-deoxyribose sugar units generating C5′ radicals, then cyclization with the C8 position of the purine base [11].

Although there were studies examining the levels of 8-OH-dG in brain tumor tissues or peripheral blood samples of glioma patients by immunohistochemistry (IHC) or high performance liquid chromatography (HPLC), no study reported mass spectrometric measurement of oxidatively-induced DNA lesions, especially in urine samples of glioma patients [12] [13]. Additionally, it has not been investigated whether DNA damage products vary according to the IDH mutation status in glial tumor patients. Evaluation of DNA damage in IDH wild-type and mutant groups in glioma patients is important in terms of monitoring the process of the disease and deciding the effectiveness of the treatment. In this study, we measured 8-OH-dG, S-cdA and R-cdA in urine samples of IDH wildtype and mutant glioma patients by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with stable-isotope dilution (SID). We also investigated the potential relationship of all findings to follow-up parameters such as tumor recurrence and patient survival.

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