Abstract 1133: Molecular evolution patterns in primary versus recurrent adult gliomas: A multi-institutional study from Project GENIE

Abstract Introduction: Gliomas are the most common primary malignant brain tumors in adults, with high recurrence rates despite multimodal treatment. While previous multi-institutional genomic studies have revealed molecular differences between primary and recurrent tumors, the AACR Project GENIE dataset provides another valuable resource to investigate these distinctions. Methods: We analyzed 8, 959 adult glioma cases from Project GENIE v16.1 (2024), selecting cases with complete mutation and copy number alteration (CNA) data. Tumors were stratified by Isocitrate dehydrogenase (IDH) mutation status, as IDH-wildtype and IDH-mutant gliomas have distinct molecular profiles and patterns of progression. The IDH-mutant cohort (n=2, 635) comprised 79.9% primary tumors (n=2, 097) and 20.1% recurrent tumors (n=538). The IDH-wildtype cohort (n=5, 885) included 89.8% primary tumors (n=5, 290) and 10.2% recurrent tumors (n=595). We examined the top 10 mutated somatic genes and compared mutational frequencies and copy number variations between primary and recurrent tumors using Fisher's exact test with Benjamini-Hochberg correction. Results: In IDH-mutant gliomas, recurrent tumors showed increased mutations across multiple genes, particularly in KMT2D (7.8% to 20.6%, OR 3.06, p<0.001), NF1 (5.25% to 13.8%, OR 2.79, p<0.001) and NOTCH1 (12.4% to 23.6%, OR 2.18, p<0.001). In IDH-wildtype gliomas, the most notable changes were observed in CIC (21.65% to 32.71%, OR 2.12, p<0.001) and SMARCA4 (6.82% to 13.75%, OR 2.36, p<0.001). Oncogenic drivers like TP53 (p>0.05) and PTEN (p>0.05) maintained stable mutation frequencies between primary and recurrent tumors in both IDH cohorts. Copy number alterations for all examined genes showed no significant differences between primary and recurrent tumors in either IDH group. Conclusion: Analysis of this large real-world dataset reveals molecular evolution patterns that align with previous observations, particularly in the stability of copy number alterations in driver genes between primary and recurrent tumors across both IDH groups. Similarly, oncogenic drivers like TP53 and PTEN maintained stable mutation frequencies, indicating preservation of critical growth-promoting pathways during glioma progression. Recurrent IDH-mutant tumors showed high mutational variance in chromatin regulators like KMT2D as well as developmental pathway gene NOTCH1. Recurrent IDH-wildtype gliomas showed more modest increases in mutational frequencies compared to primary counterparts, indicating less selective pressure from treatment in these more aggressive tumors. While the unbalanced distribution of primary versus recurrent samples and potential sampling biases inherent in real-world data limit the generalizability of these findings, these patterns may inform future therapies. Further validation in independent cohorts is warranted. Citation Format: Abhishek Bhattacharya, Anand Kornepati. Molecular evolution patterns in primary versus recurrent adult gliomas: A multi-institutional study from Project GENIE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1133.