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Loss of CDKN2A/B is a Hallmark of RTK II Glioblastomas
Celina K Langwieder1, Dorothee Hölzl1, Georg Hutarew1
1Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Müllner Hauptstr. 48, A-5020 Salzburg, Austria.
Abstract:
Glioblastomas represent the most prevalent primary brain tumors in adults. Due to their highly malignant biological behavior, they are classified as grade 4 according to the World Health Organization (WHO) classification of brain tumors. Despite the progress in understanding the molecular pathogenesis of these tumors, no curative therapy has been developed for patients with glioblastoma. In this study, an integrated comparative analysis of cyclin-dependent kinase inhibitor (CDKN) 2A/B chromosomal deletion was performed on 45 glioblastomas, representing the most frequent molecular subtypes of glioblastomas, receptor tyrosine kinase (RTK) I (n=13), RTK II (n=15), and the mesenchymal subtype (MES) (n=17). The analysis of copy number variation (CNV) profiles was conducted on CDKN2A/B losses. Subsequent statistical analysis was then applied to correlate the collected data with molecular glioblastoma epigenotypes. Loss of CDKN2A/B was found 44% (20/45) of all glioblastomas, thereby, in 46% (6/13) of RTK I, 67% (10/15) RTK II, and 24% (4/17) of MES. Statistical analysis showed that loss of CDKN2A/B is significant (p < 0.01) in RTK II compared with MES. Even though CDKN2A/B does not per se function as a molecular target, there is great potential for enhancing treatment outcomes through the restoration of the tumor-suppressing capabilities of CDKN2A/B. This strategy can be employed in therapeutic interventions and is a promising avenue for research. This efficacy of this approach demonstrates high potential, as evidenced by its efficacy in other tumors, including melanoma.
Insights
Loss of cyclin-dependent kinase inhibitor (CDKN) 2A/B occurs in 44% of glioblastomas, significantly more in the RTK II subtype. Restoring CDKN2A/B tumor-suppressing functions offers therapeutic potential.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Glioblastomas are aggressive WHO grade 4 primary brain tumors.
- Current glioblastoma therapies lack curative potential despite advances in understanding molecular pathogenesis.
- Cyclin-dependent kinase inhibitor (CDKN) 2A/B is frequently altered in various cancers.
Purpose of the Study:
- To investigate the frequency and significance of cyclin-dependent kinase inhibitor (CDKN) 2A/B chromosomal deletion across major glioblastoma molecular subtypes.
- To correlate CDKN2A/B copy number variations with glioblastoma epigenotypes.
- To explore the therapeutic potential of restoring CDKN2A/B tumor-suppressing functions.
Main Methods:
- Comparative analysis of cyclin-dependent kinase inhibitor (CDKN) 2A/B chromosomal deletion in 45 glioblastomas.
- Categorization of glioblastomas into receptor tyrosine kinase (RTK) I, RTK II, and mesenchymal (MES) subtypes.
- Copy number variation (CNV) analysis and statistical correlation with molecular epigenotypes.
Main Results:
- Loss of CDKN2A/B was observed in 44% (20/45) of all glioblastomas analyzed.
- CDKN2A/B loss occurred in 46% of RTK I, 67% of RTK II, and 24% of MES subtypes.
- Statistical analysis revealed a significant association (p < 0.01) between CDKN2A/B loss and the RTK II subtype compared to the MES subtype.
Conclusions:
- Loss of CDKN2A/B is a frequent event in glioblastomas, particularly in the RTK II subtype.
- Restoring the tumor-suppressing activity of CDKN2A/B presents a promising therapeutic strategy for glioblastoma.
- The efficacy of CDKN2A/B restoration has been demonstrated in other cancers, supporting its potential in glioblastoma treatment.
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