Abstract 6633: Survival implications of <i>CDKN2A/2B</i> deletion, <i>MET</i> amplification and <i>PIK3R1</i> mutation in adult type diffuse glioma

Abstract Diffuse gliomas, the most common primary brain tumors, present significant variations in morphology, location, genetic alterations, and treatment responses. However, the relationship between their molecular profiles and disease outcomes remains poorly understood. This study analyzed 470 primary diffuse glioma samples collected between 2017 and 2021 using the next-generation sequencing Oncopanel AMC, following the 2021 WHO criteria, to classify the tumors and analyze their clinical impact on overall survival. Statistical analyses included multivariable Cox regression, reporting hazard ratios (HR) with 95% confidence intervals (95% CI), and Kaplan-Meier survival analysis. The classification resulted in three subtypes: oligodendroglioma (n=68), diffuse astrocytoma (n=63), and glioblastoma (n=339). The median age of glioblastoma patients (64 years) was higher compared with oligodendroglioma (50 years) and diffuse astrocytoma (41 years). Gender and tumor mutational burden showed no significant association with subtypes. Oligodendroglioma was characterized by IDH mutations and 1p/19q co-deletion (100%), with frequent mutations in NOTCH1 (27.9%), FUBP1 (20.6%), and ARID1A (19.1%). Diffuse astrocytoma was marked by IDH mutations (100%) and high prevalence of mutations in TP53 (92.1%) and ATRX (79.4%). Glioblastoma showed CDKN2A/2B loss (52.5%), EGFR amplification (30.4%), and TP53 mutation (35.1%). The incidence of MTAP loss identified using specific version of the Oncopanel was observed to be 2.4% in oligodendroglioma, 14.3% in diffuse astrocytoma, and 45.4% in glioblastoma, with no significant association observed with survival. The median overall survival from the diagnosis were 30.7 months for oligodendroglioma, 27.8 months for diffuse astrocytoma, and 14.9 months for glioblastoma. In glioblastoma patients, a multivariable Cox regression analysis identified significant survival factors: older age≥60years (HR=1.35 [1.03-1.76], p=0.031), lack of MGMT promoter methylation (HR [95% CI]=1.53 [1.16-2.02], p=0.003), impaired performance status (HR [95% CI]=1.68 [1.30-2.16], p=7.03×10-5), bilateral disease (HR [95% CI]=1.71 [1.13-2.57], p=0.010), PIK3R1 mutation (HR [95% CI]=1.52 [1.05-2.18], p=0.025), CDKN2A/2B deletion (HR [95% CI]=1.41 [1.09-1.83], p=0.010), and MET amplification (HR [95% CI]=2.33 [1.19-4.54], p=0.013). This study provides insights for improved understanding and potential targeted therapies based on genetic profiling of diffuse gliomas, particularly highlighting the prognostic significance of CDKN2A/2B deletion, MET amplification, and PIK3R1 mutation in glioblastoma. These findings may guide future clinical trials drug repurposing, potentially leading to improved outcomes for patients with diffuse gliomas. Citation Format: Yongjae Kim, Soyoung Park, Soo Jeong Nam, Kang-Seo Park, Ji Eun Park, Hye Hyeon Moon, Chang Ohk Sung, Sang Woo Song, Young-Hoon Kim, Chang-Ki Hong, Jeong Hoon Kim, Shinkyo Yoon, Ho-Su Lee. Survival implications of CDKN2A/2B deletion, MET amplification and PIK3R1 mutation in adult type diffuse glioma [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 6633.