Abstract C037: Comprehensive genomic profiling in central nervous system tumors reveals low frequency of deleterious alterations in <i>SETD2</i> without associated increase in mutational burden

Abstract Background: SETD2 is a tumor suppressor gene responsible for trimethylation of H3K36, crucial for DNA mismatch repair and homologous recombination. Novel synthetic lethality agents, ATR inhibitors (ATRi), have demonstrated anti-tumor activity in preclinical models and early clinical trials for pan-tumors. SETD2 and H3K36 deficient cells have been demonstrated to display Micro Satellite Instability (MSI) with increased tumor mutational burden (TMB). Deleterious SETD2 alterations occur in 5-10% of brain tumor patients with glioblastoma, IDH wild type, WHO grade 4, (GBM). These patients have a poor prognosis. This study aims to evaluate targeted treatment strategies in central nervous system (CNS) tumors, by investigating the potential of ATRi for tumors harboring deleterious SETD2 alterations and immuno-therapy for tumors with increased mutational burden, with the objective of improving patient outcomes. Materials &amp; methods: This study analyzes genomic profiles from 434 patients diagnosed with central nervous system (CNS) tumors between January 1st, 2019, and February 28th, 2025, enrolled in the prospective Neurogenome and CoPPO studies. Rigshospitalet has one of the largest single-institution datasets with comprehensive data on SETD2 alterations derived from whole exome/genome sequencing including structural variants, copy number variations, and RNA expression. Results: The study cohort included 434 patients with CNS tumors (166 female, 268 male) with a median age at diagnosis of 59 years (interquartile range: 49-66 years). GBM was the predominant tumor type (86%), followed by astrocytoma, IDH mutated (mut), WHO grade 2-4 (12%) and oligodendroglioma, IDH-mut, 1p/19q co-deletion, WHO-grade 2-3 (1.2%). Other CNS tumors were diagnosed in 6 (1.4%) patients. Deleterious SETD2 alterations were found in 13 (3%) patients: 11 with GBM, 1 astrocytoma IDH mut, and 1 oligodendroglioma. Twelve patients had mutations: 6 premature stop codons, 5 frameshift mutations and 1 splice site variant, and one case with biallelic SETD2 loss. Data on tumor mutational burden (TMB) was assessable for 12 SETD2-deficient patients, none exceeding 10mut/mb; mean TMB was 3.3 mut/mb vs. 6.2 mut/mb in the SETD2-wildtype (wt) group. No SETD2-deficient patients had received temozolomide (TMZ) treatment prior to sampling. By contrast, some samples in the SETD2-wt cohort were obtained at relapse, which may have inflated TMB due to TMZ treatment. COSMIC signatures were available for 10 SETD2-deficient patients with none having indications of MSI based on COSMIC signature evaluation. Conclusion: Loss of SETD2 function in primary CNS-tumors is relatively rare and was predominantly driven by mutations, with copy number analysis revealing only 1 biallelic deletion in 434 patients. SETD2 alterations was primarily seen in GBM patients. The SETD2 deficient patients did not exhibit indications of MSI or high TMB. However, the impact of patient relapse samples with TMZ induced mutations in the SETD2-wt cohort is being explored further together with pan-tumor markers for DNA damage repair. Citation Format: Tine Østergaard, Christoffer L. Halvorsen, Dorte S. Nørøxe, Vincent N. Fougner, Iben Spanggaard, Kristoffer S. Rohrberg, Martin Højgaard. Comprehensive genomic profiling in central nervous system tumors reveals low frequency of deleterious alterations in SETD2 without associated increase in mutational burden [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C037.