ID #484 Exploring the Genomic Correlates of Necrosis in Diffuse Intrinsic Pontine Glioma

Abstract

Diffuse intrinsic pontine gliomas (DIPG), a subset of diffuse midline glioma, are highly aggressive tumors of the pons that have an average survival of 12 months after diagnosis[1]. Magnetic resonance imaging (MRI) is the gold standard for DIPG diagnosis and monitoring. Thus, recent studies have focused on identifying MRI features that may help distinguish DIPG patients likely to have poor responses to therapy or early tumor progression. In a preliminary study investigating DIPG MRI features, we found that tumors with heightened levels of T1-enhancement (>20% by volume) are associated with a shorter overall survival[2]. However, the relationship between this MRI feature, which is indicative of necrosis, and the tumor’s genetic profile remains poorly understood. This study aims to identify oncogenic variants that are associated with high levels of necrosis in DIPG.

MRI images and sequencing data from DIPG patients were acquired through the Children’s Brain Tumor Network, the Lurie Children’s HONT Biorepository, and Children’s National Hospital (n = 49). Volumetric measurements from T1 post-contrast and T2 MRIs were recorded for each tumor at diagnosis and approximately 6 weeks post-radiation therapy. Based on prior studies, tumors with greater than 20% T1-enhancement by volume were identified as necrosis-high[2]. Pathogenic variants were identified in each tumor and compared to uncover shared genetic features within the necrosis-high and necrosis-low groups.

Preliminary data suggests that PPM1D and co-occurring PI3K pathway mutations (PIK3CA, PIK3R1) are more common in the necrosis low group. Inversely, PTEN mutations, previously associated with poor survival in DIPG, are more frequent in the necrosis-high group.

These results suggest that necrosis-low and necrosis-high DIPG tumors have different genomic signatures. This information may be used to improve targeted treatments in the future. Additional studies will expand our sample size and include analysis of structural variants and non-genetic features to create a more holistic picture of these tumors.

1. Cooney T, Lane A, Bartels U, Bouffet E, Goldman S, Leary SES, Foreman NK, Packer RJ, Broniscer A, Minturn JE, Shih CS, Chintagumpala M, Hassall T, Gottardo NG, Dholaria H, Hoffman L, Chaney B, Baugh J, Doughman R, Leach JL, Jones BV, Fouladi M, Warren KE, Monje M. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro Oncol. 2017 Sep 1;19(9):1279-1280. doi: 10.1093/neuonc/nox107. PMID: 28821206; PMCID: PMC5570207.

2. Spencer D, Bonner ER, Tor-Díez C, Liu X, Bougher K, Prasad R, Gordish-Dressman H, Eze A, Packer RJ, Nazarian J, Linguraru MG, Bornhorst M. Tumor volume features predict survival outcomes for patients diagnosed with diffuse intrinsic pontine glioma. Neurooncol Adv. 2024 Aug 30;6(1):vdae151. doi: 10.1093/noajnl/vdae151. PMID: 39434924; PMCID: PMC11492488.