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. 2025 Mar 7;27(3):743-754.
doi: 10.1093/neuonc/noae238.

The prognostic impact of CDKN2A/B hemizygous deletions in IDH-mutant glioma

Franziska M Ippen  1   2   3 , Thomas Hielscher  4 , Dennis Friedel  5   6   2 , Kirsten Göbel  6   2 , David Reuss  6   2 , Christel Herold-Mende  7   8 , Sandro Krieg  7 , Andreas V Deimling  6   2 , Wolfgang Wick  9   3 , Felix Sahm  6   2 , Abigail K Suwala  6   2
Affiliations

The prognostic impact of CDKN2A/B hemizygous deletions in IDH-mutant glioma

Franziska M Ippen et al. Neuro Oncol. .

Abstract

Background: Homozygous deletions of CDKN2A/B are known to predict poor prognosis in gliomas, but the impact of hemizygous deletions is less clear. This study aimed to evaluate the prognostic significance of hemizygous CDKN2A/B deletions in IDH-mutant low-grade astrocytomas and oligodendrogliomas.

Methods: Tissue samples diagnosed as astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3 were collected from the archives of the Institute of Neuropathology in Heidelberg. DNA methylation analysis was performed on formalin-fixed paraffin-embedded samples. Evaluation of the CDKN2A/B locus was performed by visual inspection of copy-number plots derived from methylation-array data for each case. Hemizygous and homozygous losses were assessed in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan-Meier method.

Results: A total of 334 low-grade glioma cases were identified, including 173 astrocytomas and 161 oligodendrogliomas. Hemizygous deletions in CDKN2A/B (37/173 in astrocytomas, 15/161 in oligodendrogliomas) did not confer significantly worse survival outcomes compared to CDKN2A/B wild-type cases in neither low-grade astrocytoma (log-rank P = .2556; HR 2.29, 95% CI [0.76; 6.40], P = .135) nor oligodendroglioma (log-rank P = .2760; HR 0.17; 95% CI [0.01; 5.05]; P = .305), regardless of CNS WHO grade, which was further demonstrated on a subgroup of astrocytoma, IDH mutant CNS WHO 4 cases (log-rank P = .1680; HR 4.55, 95% CI [0.88; 24.51], P = .0689).

Conclusions: Hemizygous CDKN2A/B deletions do not significantly worsen OS or progression-free survival in IDH-mutant astrocytomas and oligodendrogliomas, CNS WHO grades 2 and 3.

Keywords: CDKN2A/B; IDH-mutant glioma; hemizygous deletion; survival.

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Conflict of interest statement

All authors declare no potential conflicts of interest. Av.D. and F.S. are co-founders and shareholders of Heidelberg Epignostix GmbH.

Figures

Figure 1.
Figure 1.
The inclusion and exclusion criteria of the study cohort (Heidelberg cohort) were investigated to assess the prognostic impact of hemizygous CDKN2A/B deletions. Abbreviations: MC, methylation class; IDH, Isocitrate dehydrogenase; WHO, World Health Organization; het del, hemizygous deletion; homo del, homozygous deletion.
Figure 2.
Figure 2.
Hemizygous deletions in CDKN2A/B do not confer worse overall survival outcomes in IDH-mutant astrocytomas CNS WHO grade 2 and 3 (Heidelberg cohort). Overall survival (OS) in percent for (A) low-grade astrocytomas CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion; (B) astrocytomas CNS WHO 2 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion; (C) astrocytomas CNS WHO 3 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion Abbreviations: wt, wild type; CNS, central nervous system; IDH, Isocitrate dehydrogenase; WHO, World Health Organization.
Figure 3.
Figure 3.
Hemizygous deletions in CDKN2A/B do not confer worse progression-free survival outcomes in IDH-mutant astrocytomas WHO grade 2 and 3 (Heidelberg cohort). Progression-free survival (PFS) in percent for (A) low-grade astrocytomas CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion; (B) astrocytomas CNS WHO 2 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion; (C) astrocytomas CNS WHO 3 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion Abbreviations: wt, wild type; CNS, central nervous system; IDH, Isocitratdehydrogenase; WHO, World Health Organization.
Figure 4.
Figure 4.
Hemizygous deletions in CDKN2A/B do not account for worse overall survival in IDH-mutant oligodendrogliomas CNS WHO grade 2 and 3 (Heidelberg cohort). Overall survival (OS) in percent for (A) oligodendrogliomas CNS WHO 2 and 3 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion; (B) oligodendrogliomas CNS WHO 2 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion; (C) oligodendrogliomas CNS WHO 3 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion Abbreviations: wt, wild type; CNS, central nervous system; IDH, Isocitratdehydrogenase; WHO, World Health Organization.
Figure 5.
Figure 5.
Hemizygous CDKN2A/B deletions do not result in diminished progression-free survival in IDH-mutant oligodendrogliomas WHO grade 2 and 3 (Heidelberg cohort). Progression-free survival (PFS) in percent for (A) oligodendrogliomas WHO 2 and 3 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion; (B) oligodendrogliomas CNS WHO 2 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion; (C) oligodendrogliomas CNS WHO 3 CDKN2A/B wild type vs. with a hemizygous CDKN2A/B deletion. Abbreviations: wt, wild type; CNS, central nervous system; IDH, Isocitratdehydrogenase; WHO, World Health Organization.
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