PATH-18. Investigating the role of CDKN2A loss in IDH-mutant gliomas: biological insights beyond tumour grading

Abstract CDKN2A/B homozygous deletion (HoD) in IDH-mutant astrocytomas is associated with poor prognosis and now defines WHO grade 4 status, regardless of histology. We hypothesized that CDKN2A loss resulting from CDKN2A/B HoD drives biological changes independent of morphological grade. To explore this, we first analysed TCGA transcriptomic datasets and found that CDKN2A HoD astrocytomas exhibit marked cell cycle dysregulation compared to non-deleted cases. However, given the overrepresentation of morphological grade 4 features in HoD tumors, we assembled a unique cohort of IDH-mutant astrocytomas matched for morphological grade, with and without CDKN2A deletion. This analysis confirmed that CDKN2A deletion is independently associated with cell cycle-related transcriptional changes. We then performed single cell RNA sequencing on a cohort of IDH-mutant astrocytomas and found that lost or low CKDN2A expression is associated with known drivers of cell growth, DNA replication and neuronal stemness. To functionally validate the role of CDKN2A loss, we generated CDKN2A knock-in (KI) models in multiple CDKN2A-null, IDH-mutant glioma cell lines. Metabolomic profiling revealed that CDKN2A-null cells had elevated 2-hydroxyglutarate and reduced glutamate and glutamine levels. Transcriptomic profiling together with gene set enrichment and Ingenuity Pathway Analysis confirmed cell cycle dysregulation and revealed enrichment of immune related pathways and upregulation of neuronal stem markers in CDKN2A-null cells. Functionally, CDKN2A-null cells were more sensitive to temozolomide, displaying increased G2/M arrest and apoptosis. In contrast, CDKN2A KI cells showed resistance to temozolomide, and increased expression of the senescence marker β-galactosidase. Our findings suggest that homozygous CDKN2A loss alters the behaviour of IDH-mutant astrocytomas irrespective of morphological grade. Ongoing studies using orthotopic xenografts and patient-derived models aim to further validate these findings.

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Publication Details

Journal
Neuro-Oncology
Published
2025-11-01
DOI
https://doi.org/10.1093/neuonc/noaf201.0970
Primary Topic
Glioma Diagnosis and Treatment
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article
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article

PATH-18. Investigating the role of CDKN2A loss in IDH-mutant gliomas: biological insights beyond tumour grading

Razia Zakarya, Cecilia Escher, Ashraf Zaman, Isabella Wilson et al.
Neuro-Oncology
Glioma Diagnosis and Treatment
article

PATH-18. Investigating the role of CDKN2A loss in IDH-mutant gliomas: biological insights beyond tumour grading

Razia Zakarya, Cecilia Escher, Ashraf Zaman, Isabella Wilson, Hao‐Wen Sim, Joe Wei, Angela Bayly, Anthony James Gill, Laveniya Satgunaseelan, David Lok Hang Chan, Benjamin Y. Kong, Amanda L. Hudson, Michael Back, Subotheni Thavaneswaran, Michael E. Buckland, Marina Kastelan, Alexander Yuile, Joseph E. Powell, Helen Wheeler, Heng Wei, Adrian Lee, Kimberley L. Alexander, Winny Varikatt, Alice Meng, Mark Wong, Michael Rodriguez, Zarnie Lwin, Nick Pavlakis, Hwei Choo Soh, Maggie Lee
article en

Abstract

Abstract CDKN2A/B homozygous deletion (HoD) in IDH-mutant astrocytomas is associated with poor prognosis and now defines WHO grade 4 status, regardless of histology. We hypothesized that CDKN2A loss resulting from CDKN2A/B HoD drives biological changes independent of morphological grade. To explore this, we first analysed TCGA transcriptomic datasets and found that CDKN2A HoD astrocytomas exhibit marked cell cycle dysregulation compared to non-deleted cases. However, given the overrepresentation of morphological grade 4 features in HoD tumors, we assembled a unique cohort of IDH-mutant astrocytomas matched for morphological grade, with and without CDKN2A deletion. This analysis confirmed that CDKN2A deletion is independently associated with cell cycle-related transcriptional changes. We then performed single cell RNA sequencing on a cohort of IDH-mutant astrocytomas and found that lost or low CKDN2A expression is associated with known drivers of cell growth, DNA replication and neuronal stemness. To functionally validate the role of CDKN2A loss, we generated CDKN2A knock-in (KI) models in multiple CDKN2A-null, IDH-mutant glioma cell lines. Metabolomic profiling revealed that CDKN2A-null cells had elevated 2-hydroxyglutarate and reduced glutamate and glutamine levels. Transcriptomic profiling together with gene set enrichment and Ingenuity Pathway Analysis confirmed cell cycle dysregulation and revealed enrichment of immune related pathways and upregulation of neuronal stem markers in CDKN2A-null cells. Functionally, CDKN2A-null cells were more sensitive to temozolomide, displaying increased G2/M arrest and apoptosis. In contrast, CDKN2A KI cells showed resistance to temozolomide, and increased expression of the senescence marker β-galactosidase. Our findings suggest that homozygous CDKN2A loss alters the behaviour of IDH-mutant astrocytomas irrespective of morphological grade. Ongoing studies using orthotopic xenografts and patient-derived models aim to further validate these findings.

Neuro-OncologyVol. 27(Supplement_5)
University of Technology Sydney (AU), The University of Sydney (AU), New South Wales Department of Health (AU), Garvan Institute of Medical Research (AU), The University of Queensland (AU), Walsh University (US), Royal Prince Alfred Hospital (AU), Royal North Shore Hospital (AU), Woolcock Institute of Medical Research (AU), Sydney Hospital (AU), Westmead Hospital (AU), UNSW Sydney (AU), St Vincent's Hospital Sydney (AU), Cancer Australia (AU), Futures Group (United States) (US), Prince of Wales Hospital (AU), Migration Institute of Australia (AU), Horticulture Innovation Australia (AU), Sydney Local Health District (AU), The Kinghorn Cancer Centre (AU), National Health and Medical Research Council (AU), Macquarie University (AU)
Openalex Percentile: Top 51%
Glioma Diagnosis and Treatment
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