CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review

Abstract

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations-heterozygous deletions (HeD), point mutations, and promoter methylation-is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker.

Keywords: CDKN2A/B alterations; CDKN2A/B heterozygous deletions; CDKN2A/B homozygous deletions; IDH mutant glioblastomas; grade 4 astrocytomas; radiotherapy; temozolomide.

Figure 1

Flow diagram summarising the WHO Classification of CNS Tumours (fifth edition, 2021) [14] and the role of CDKN2A/B HD (red box). Note: gain 7/loss 10 refers to the gain of chromosome 7 and the loss of chromosome 10.

Figure 2

Diagram showing the locations of CDKN2A/B and other relevant genes on the 9p21.3 locus. Adapted from the National Institute of Health, National Library of Medicine: Genome Data Viewer [38].

Figure 3

Diagram showing the anti-proliferative and anti-angiogenic effects of CDKN2A/B Mouse double minute 2 homolog (MDM2), tissue inhibitor of metalloproteinase 3 (TIMP3), matrix metalloproteinases (MMP), retinoblastoma protein (Rb), vascular endothelial growth factor (VEGF), and cyclin-dependent kinases (CDK).