<i>MTAP</i> deletions and co-mutational landscape from whole genome sequencing in primary CNS tumors.

Abstract

3117 Background: Biallelic deletions of the MTAP (methylthioadenosine phosphorylase) gene are frequent in solid tumors and confer synthetic lethality to PRMT5 (protein arginine methyltransferase 5) inhibition. Clinical trials are exploring the safety and efficacy of PRMT5 inhibitors (PRMT5i). Targeting additional co-occurring actionable alterations, such as gain-of-function mutations, with kinase inhibitors in combination with MTAP -directed synthetic lethality may potentiate therapeutic efficacy. MTAP deletions are present in up to 40% of glioblastomas (GBM) and occur sporadically in other primary central nervous system (CNS) tumors. Identification of actionable targets beyond MTAP deletions could enable combination strategies in these diagnoses, with otherwise limited therapeutic options. Whole-genome sequencing (WGS) with exon-level copy number alteration (CNA) analysis allows accurate determination of MTAP status, assessment of concordance with copy number variations (CNVs) in the neighboring CDKN2A and CDKN2B genes, and evaluation of the prevalence of co-occurring actionable alterations (including IDH1, KRAS, PIK3CA, FGFR, and NTRK alterations). Methods: A total of 145 consecutive patients with primary WHO grade 4 gliomas or other primary CNS tumors underwent WGS at the time of diagnosis as part of the prospective Neurogenome Study at Copenhagen University Hospital between January 2023 and October 2025. 57 patients (39%) were female, and the median age was 59 years (range, 26–78). MGMT promoter methylation was detected in 59 patients (40.4%); 6 tumors were not evaluable for MGMT status. 130 cases (GBM, n=118; astrocytoma, IDH -mutant, n=12) had reliable MTAP copy number analysis, samples with e.g. high fraction of normal tissue where excluded from analysis. Results: Among the 130 evaluable cases, 52 (40%) harbored biallelic MTAP deletions, 37 (28%) had monoallelic deletions, and 39 (30%) had no MTAP deletions. 2 cases (1.5%) had deletion of one MTAP allele with partial deletion of the second allele (exon-level deletions). Concordance between MTAP CNVs and CDKN2A/ B CNVs—defined as either biallelic deletion or non-biallelic deletion of both MTAP and CDKN2A/B genes—was observed in 113 of 130 cases (87%). 31 cases harbored additional potentially actionable alterations. In tumors with biallelic MTAP deletions, 9 cases contained co-occurring actionable targets ( FGFR fusion 1; KRAS mutation 1; NTRK fusion 1; PIK3CA mutation 4; IDH1 + PIKCA3 mutations 1; IDH1 mutation + PTPRZ1-MET fusion 1). Conclusions: MTAP biallelic deletions were frequent at diagnosis in this primary CNS tumor population, whereas partial deletions of the MTAP gene (exon deletions) were rare. High concordance with CDKN2A/B status on WGS was observed. A subset of cases with biallelic MTAP deletions harbored other actionable targets underscoring the potential for combining PRMT5i with other targeted agents.