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This study aims to characterize the mutational landscape of diffuse intrinsic pontine glioma (DIPG) and identify potential therapeutic targets.

May 30, 2026

Genomic profiling of diffuse intrinsic pontine glioma in AACR Project GENIE.

Key Points

This study aims to characterize the mutational landscape of diffuse intrinsic pontine glioma (DIPG) and identify potential therapeutic targets.
Utilized AACR Project GENIE database to analyze 240 DIPG samples from 227 patients.
Conducted somatic point mutations and copy number alterations analysis using statistical methods including T-tests and non-parametric tests.
Performed demographic correlations by race and sex, identifying mutation frequencies and specific gene alterations.
H3F3A mutations were found in 72.1% (n=173) of samples, indicating its role as a key driver of DIPG.
Significant sex-based differences were noted, with ACVR1 mutations more prevalent in females (n=21) versus males (n=8; p<0.05).
Race-specific alterations included exclusive gene mutations in Black patients (p<0.01) and more frequent BRCA2 mutations compared to other racial groups (p<0.05).

Abstract

e14070 Background: Diffuse intrinsic pontine glioma (DIPG) is an aggressive high-grade glioma, originating in the pons and primarily affecting children <10 years of age. Surgical resection is rarely feasible and median survival with radiation remains <1 year. Prior studies indicate histone H3 epigenetic dysregulation driving DIPG but data are limited to small institutional cohorts. This study leverages the American Association for Cancer Research (AACR) Project Genomic Evidence Neoplasia Information Exchange (GENIE) database to characterize DIPG’s mutational landscape and identify possible therapeutic targets. Methods: The AACR Project GENIE database was accessed from cBioPortal (v18.0-public) on November 25, 2025 to identify patients and samples with confirmed DIPG. Somatic point mutations, copy number alterations, demographic correlations, and mutual exclusivities were analyzed using a two-sided T-test and non-parametric tests, with Benjamini-Hochberg False Discovery Rate correction. Unknown and Other values were excluded. Results: The cohort comprised 240 DIPG samples from 227 patients. Males (n=106, 46.7%) and females (n=113, 49.8%) were similarly affected, and most patients were pediatric (n=197, 86.8%). By race, the cohort consisted of White (n=72, 31.7%), Black (n=16, 7.0%), and Asian (n=12, 5.3%) patients. Samples were collected from primary (n=202, 84.2%) and metastatic (n=12, 5.0%) tumors. The most frequent somatic mutations were observed in H3F3A (n=173, 72.1%), TP53 (n=116, 48.3%), ATRX (n=37, 15.4%), PIK3CA (n=35, 14.6%), PPM1D (n=34, 14.2%), NF1 (n=31, 12.9%), TERT (n=29, 12.1%), ACVR1 (n=29, 12.1%), and HIST1H3B (n=25, 10.4%). Sex-stratified analysis demonstrated a higher frequency of ACVR1 mutations in females compared to males (n=21 vs. n=8; p<0.05), while KMT2C mutations were more frequent in males (p<0.05). Race-based analysis identified several genes detected exclusively in Black patients, including LRP1B , MAP3K9 , and ERBB3 (p<0.01), and BRCA2 mutations were more frequent in Black patients compared with Asian and White patients (p<0.05). In Asian patients, ZFPM1 and RET mutations were observed exclusively (p<0.05). Among frequently altered genes, H3F3A and TP53 mutations demonstrated significant co-occurrence (p<0.05). Stratification by tumor site demonstrated increased prevalence of SLX4 and TET1 mutations in primary tumors (p<0.001), while PIK3R2 mutations were more frequent in metastatic samples (p<0.05). Conclusions: This study demonstrates H3F3A as a key molecular driver of DIPG, highlighting the role of histone H3 epigenetic dysregulation in prior studies. Co-occurrence of H3F3A and TP53 suggests cooperative oncogenic pathways. Sex-based differences (e.g., ACVR1 and KMT2C ) and race-specific alterations emphasize demographic influence on molecular heterogeneity. These results further support H3F3A and its signaling pathways as therapeutic targets in DIPG.

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