Understanding Patterns of Co-deletion Cdkn2a/b Deleted Gbm to Support a Synthetic Lethality Approach to Treatment
Year: 2025
Type: article
Abstract: AIMS CDKN2A/B homozygous deletion is among the most common genetic alterations in glioblastoma (GBM), often accompanied by losses of neighbouring tumour suppressors such as MTAP and PTPRD. These co-deletions create vulnerabilities that may be exploited for synthetic lethality-based therapies. While recent network analysis has demonstrated the potential of combination therapy to target such synthetic lethal nodes, the underlying patterns of co-deletion and their downstream molecular effects remain unclear. We conducted a multi-omics analysis to systematically assess these co-deletion patterns and their functional consequences in CDKN2A/B-deleted GBM. METHODS Copy number variation (CNV), whole exome sequencing (WES), mRNA expression, and reverse-phase protein array (RPPA) data from TCGA-GBM (n=63) and CPTAC (n=96) were analysed. Patients with significant CDKN2A/B losses were identified using GISTIC2.0 and assessed for co-occurring alterations in MTAP, PTPRD, and EGFR and broader 9p21 losses using Fisher’s Exact test. Downstream mRNA and protein expression changes were evaluated with Mann-Whitney U tests. RESULTS CDKN2A/B homozygous deletion was strongly associated with MTAP loss (TCGA-GBM: 74.6%; CPTAC: 83.0%), moderate PTPRD loss (TCGA-GBM: 55.6%; CPTAC: 30.8%), and moderate EGFR amplification (TCGA-GBM: 55.6%; CPTAC: 60.4%). Complete 9p21 loss was common (TCGA-GBM: 54.9%; CPTAC: 35.4%) but deletion proportions varied within and across cohorts. CDKN2A/B-deleted patients had significant reductions in MTAP and PTPRD mRNA and protein expression (p < 0.05) and increases in EGFR mRNA and protein expression (p < 0.05) com- pared to non-deleted patients. CONCLUSION CDKN2A/B deletion is associated with broader 9p21 loss and functional changes in key synthetic lethal nodes, supporting its potential as a therapeutic biomarker. These results justify the development of synthetic lethality- based clinical trials targeting GBM with 9p21 loss. Future work will focus on functional validation of drug combinations and clinical trial design.
Source: Neuro-Oncology
Authors: Tanishi Moitra, Michael Castro, Matt Williams
Institution: Imperial College London
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4413927635