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CASE REPORT article

Front. Oncol.

Sec. Neuro-Oncology and Neurosurgical Oncology

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1557245

A Case Report on IDH-Mutant Astrocytoma, CNS WHO Grade 4: Multi-Omic Characterization of Untreated Clinical Progression

Provisionally accepted
Xiaoqin  TangXiaoqin TangWei  WeiWei WeiYanyan  HuangYanyan HuangYi  ZhengYi ZhengYajing  XuYajing XuFei  LiFei Li*
  • Department of Neurosurgery, Southwest Hospital, Chongqing, China

The final, formatted version of the article will be published soon.

Background: The natural history of untreated IDH-mutant astrocytoma, CNS WHO grade 2, progressing to astrocytoma grade 4 remains poorly characterized. Methods: A 67-year-old woman with a histologically confirmed grade 2 astrocytoma developed a spatially adjacent grade 4 lesion after eight years without therapeutic intervention. Tumor tissue and peripheral blood were analyzed using integrated genomic, transcriptomic, and immune profiling. Results: The central region retained grade 2 histology, while the peripheral region exhibited grade 4 features. Both shared mutations in IDH1, TP53, and ATRX, with highly concordant methylation patterns. The grade 4 lesion uniquely acquired mutations in CIC, BRCA2, and RPA4, and showed a 70% increase in NAF1 mutant allele frequency. Pathway analysis revealed MSP-RON and NF-κB activation, increased mast cell infiltration, and reduced IL-17 signaling, dendritic cells, and CD4⁺/CD8⁺ T-cell presence. Among the 1,926 peripheral blood T-cell receptor clonotypes, only 2.1% were detected in the tumor regions. Two highly abundant clonotypes were consistently present in peripheral blood, grade 2, and grade 4 samples, indicating clonal persistence across compartments. Conclusion: This case highlights the clonal progression of an IDH-mutant astrocytoma from grade 2 to grade 4, potentially driven by additional mutations and immune remodeling. These exploratory findings suggest candidate mechanisms of glioma evolution and may inform adoptive T-cell therapy approaches.

Keywords: Naturalevolutiondisease progression, Glioma, astrocytoma, grade 4, Isocitrate Dehydrogenase, tumor- infiltrating lymphocytes, case reports

Received: 08 Jan 2025; Accepted: 22 Aug 2025.

Copyright: © 2025 Tang, Wei, Huang, Zheng, Xu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Fei Li, Department of Neurosurgery, Southwest Hospital, Chongqing, China

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