The Prognostic Impact of CDKN2A/B Hemizygous Deletions in IDH-Mutant Glioma

Neurology Oncology Medicine
glioma IDH mutation CDKN2A/B deletion prognosis neuro-oncology

Background Introduction

Glioma is one of the most common primary tumors of the central nervous system, and its prognosis and treatment methods vary significantly depending on molecular characteristics. In recent years, with the advancement of molecular pathology, IDH (isocitrate dehydrogenase) mutations have been identified as important molecular markers in gliomas, particularly in low-grade gliomas such as astrocytomas and oligodendrogliomas. IDH-mutant gliomas generally have a better prognosis, but certain molecular alterations, such as deletions in the CDKN2A/B gene, may significantly impact patient survival.

The CDKN2A/B gene is located on the short arm of chromosome 9 (9p) and encodes several cell cycle regulatory proteins (e.g., p16, p14, and p15), which play a crucial role in tumor suppression. Current research indicates that homozygous deletions of CDKN2A/B are closely associated with poor prognosis in IDH-mutant gliomas and have been incorporated into the 2021 World Health Organization (WHO) classification of central nervous system tumors as an upgrade criterion for IDH-mutant astrocytomas. However, the prognostic significance of hemizygous deletions of CDKN2A/B remains controversial. Some studies suggest that hemizygous deletions are associated with worse survival, while others have found no significant correlation. Therefore, clarifying the prognostic value of CDKN2A/B hemizygous deletions in IDH-mutant gliomas has important clinical implications.

Source of the Paper

This study was conducted by Franziska M. Ippen, Abigail K. Suwala, and colleagues from the University Hospital Heidelberg, the German Cancer Research Center (DKFZ), and other institutions, and was published in the 2025 issue of Neuro-Oncology (Volume 27, Issue 3, Pages 743-754). The study aimed to evaluate the prognostic significance of CDKN2A/B hemizygous deletions in IDH-mutant low-grade gliomas (WHO grades 2 and 3) and explore their potential applications in clinical diagnosis and treatment.

Research Process and Results

1. Sample Collection and Classification

The research team collected tissue samples from patients diagnosed with IDH-mutant astrocytomas and 1p/19q co-deleted oligodendrogliomas between 1994 and 2022 from the archives of the Institute of Neuropathology at Heidelberg University. All samples were from initial diagnoses, excluding recurrent tumors. Ultimately, the study included 334 low-grade glioma patients, of which 173 were astrocytomas and 161 were oligodendrogliomas. Additionally, 42 cases of WHO grade 4 astrocytomas were included as a validation set.

2. DNA Methylation Analysis and CDKN2A/B Status Assessment

All samples underwent DNA methylation analysis using Illumina’s Infinium MethylationEPIC (850K) or Infinium HumanMethylation450 (450K) chips to generate raw data. The deletion status of the CDKN2A/B locus was manually assessed based on copy-number plots derived from methylation data. Hemizygous deletions were defined as copy-number reductions similar to whole-chromosome or large-segment losses, while homozygous deletions were defined as copy-number reductions twice the magnitude of single-chromosome losses.

3. Survival Analysis

The study used the Kaplan-Meier method to assess overall survival (OS) and progression-free survival (PFS) and analyzed the relationship between CDKN2A/B deletion status and prognosis using a Cox proportional hazards model. The results showed that hemizygous deletions of CDKN2A/B did not significantly affect OS or PFS in IDH-mutant astrocytomas and oligodendrogliomas. Specifically, in astrocytomas, there was no significant difference in OS (log-rank p = 0.2556) or PFS (log-rank p = 0.1280) between patients with hemizygous deletions and those without. Similarly, no significant impact on survival was observed in oligodendrogliomas (OS: log-rank p = 0.2760; PFS: log-rank p = 0.8915).

4. Validation Set Analysis

To validate these findings, the research team repeated the assessment of CDKN2A/B status in WHO grade 4 astrocytoma cases. The results showed no significant difference in OS between patients with hemizygous deletions and those without (log-rank p = 0.168), while patients with homozygous deletions had significantly worse OS (log-rank p = 0.0493). This further supports the conclusion that CDKN2A/B hemizygous deletions have limited prognostic significance in IDH-mutant gliomas.

5. Analysis of Other Molecular Markers

The study also evaluated the impact of amplifications in CDK4/6, CCND1/2, and PDGFRA genes, as well as methylation subtypes and copy-number load (CNV load) on prognosis. The results showed that amplifications in CDK4/6 and PDGFRA were significantly associated with worse OS, while CCND1/2 amplifications showed no significant impact. Stratification analysis based on methylation subtypes and CNV load also revealed significant associations with prognosis.

Conclusions and Significance

This study, through large-sample analysis and independent validation, systematically evaluated the prognostic significance of CDKN2A/B hemizygous deletions in IDH-mutant low-grade gliomas for the first time. The findings indicate that hemizygous deletions do not significantly affect OS or PFS, which contradicts some previous studies. The research emphasizes the importance of considering overall chromosomal copy-number changes when assessing CDKN2A/B status and recommends a manual evaluation method based on copy-number plots.

Additionally, the study highlights the potential prognostic value of molecular markers such as CDK4/6 and PDGFRA amplifications, providing new directions for future research on glioma molecular classification and personalized treatment. The results have significant clinical implications, aiding in more accurate prognosis assessment and guiding treatment decisions for IDH-mutant glioma patients.

Research Highlights

  1. First systematic evaluation of the prognostic significance of CDKN2A/B hemizygous deletions: Through large-sample analysis and independent validation, the study clarified the limited prognostic value of hemizygous deletions in IDH-mutant gliomas.
  2. Recommended manual evaluation method for copy-number plots: The study proposed a manual evaluation method based on methylation data, emphasizing the importance of considering overall chromosomal copy-number changes.
  3. Discovery of new prognostic markers: The study revealed the potential prognostic value of molecular markers such as CDK4/6 and PDGFRA amplifications, providing new directions for future research.

Summary

This study provides important scientific evidence for the molecular classification and prognosis assessment of IDH-mutant gliomas, with significant clinical value. The findings not only aid in more accurate prognosis assessment but also provide a theoretical basis for the future development of targeted therapies against molecular markers such as CDK4/6 and PDGFRA.