PATH-52. Understanding the prevalence of MTAP and CDKN2A/B deletion in gliomas by next generation sequencing

BACKGROUND CDKN2A/B (cyclin-dependent kinase inhibitor 2A/B) gene alterations are integral to the diagnosis and prognostication of IDH-mutant gliomas. CDKN2A/B status is commonly assessed by next generation sequencing (NGS) or inferred from loss of the surrogate marker MTAP (5’-methylthioadenosine phosphorylase) by immunohistochemistry, since the MTAP gene (located adjacent to the CDKN2A/B locus on chromosome 9p21) is often presumed deleted when CDKN2A/B is deleted. However, with MTAP deletion emerging as a therapeutic target in gliomas, directly characterising its incidence and implications is essential. METHODS The incidence of CDKN2A/B and MTAP deletions was evaluated by NGS multigene panels across glioma subtypes within the Australian national Molecular Screening and Therapeutics (MoST) and Cancer Screening Programs (CaSP). All patients with glioma (glioblastoma, astrocytoma, oligodendroglioma) enrolled between June 2017 and April 2025 were reviewed. Sequencing was performed using FoundationOne CDx, TruSight Oncology 500, TruSight Tumor 170, or AVENIO. For panels not directly assessing MTAP, a bioinformatic algorithm was used to predict deletion based on copy number variation in non-targeted regions. RESULTS Of 785 gliomas, 328 (41.8%) had CDKN2A deletion and 271 (34.5%) had CDKN2A/B codeletion. MTAP homozygous deletion, whether predicted or directly measured, was observed in 230 (70.1%) with CDKN2A deletion and in 200 (73.8%) with CDKN2A/B codeletion. MTAP deletion was not identified in the absence of CDKN2A deletion. An additional 19 patients harboured CDKN2A/B mutations without associated MTAP deletion. When stratified by IDH mutation status, CDKN2A deletion occurred in 40 of 200 IDH-mutant gliomas (20%), with co-occurring MTAP deletion in 31 cases (77.5%); and in 288 of 585 IDH-wildtype gliomas (49.2%), with co-occurring MTAP deletion in 199 (69.1%). CONCLUSIONS MTAP deletions can no longer be inferred from CDKN2A/B status alone. Beyond NGS, evaluating other methods of determining MTAP deletion status such as immunohistochemistry would be worthwhile as a cost-effective method for screening and/or validation.