Comparative Genomic and Epigenetic Landscape of Histone H3.3 G34R and K27M-Mutated Pediatric High-Grade Glioma Suggests Divergent Precision Oncology Strategies
- 1Brown University
Abstract
Histone H3-G34R and H3-K27M mutations define distinct diffuse high-grade glioma subtypes diffuse hemispheric glioma (DHG), midline (DMG), and pontine gliomas (DIPG). We characterized pathway-architectures using cBioPortal and pedcBioPortal for H3-G34R (n=112) and H3-K27M (n=727) mutated-gliomas, co-mutations, copy numbers (CNA), and variant data (n=112/727, n=86/578, n=51/313). We evaluated altered-genes as oncogenic by OncoKB, Gene-Ontology (GO) heatmaps and process-enrichment using clusterProfiler (Benjamini-Hochberg-adjusted p<0.05). H3-G34R-gliomas harbored near-universal TP53 (94.1%), ATRX (81.4%) co-mutations and PDGFRA alteration (54.9% mutation; 17.1% amplification) within 4q12 amplicon that includes KIT and KDR. Pathway-enrichment converged on G1/S cell-cycle checkpoints, and epigenetic regulation, driven principally by TP53, ATRX, PTEN, BCOR, TERT, FBXW7, and PPM1D. CDK6 amplification was rare (2.6%), despite H3-G34R association with CDK6-dependency including benefit from CDK4/6 inhibition. H3-K27M-gliomas displayed PI3K/AKT pathway activation (PIK3CA, 14.9%; NF1, 13.3%; PDGFRA, 10.8%, PIK3R1, 7.8%; PTEN, 5.7%) and developmental signatures through NF1, PTEN, and SOX10 (4.95%) mutations. TP53 (62.2%) and ATRX (21.2%) co-mutations were less frequent in H3-K27M versus H3-G34R, while PPM1D was H3-K27M-enriched (19.3%). MGMT promoter methylation occurred frequently in H3-G34R (65.2%, 15/23) versus H3-K27M-gliomas (5.4%, 4/74), despite genome-hypomethylation of H3-G34R. H3-G34R-gliomas, unlike H3-K27M, upregulated ganglionic GSX2, DLX1, DLX2, and FOXG1. SOX10 was upregulated in H3-K27M-gliomas, versus H3-G34R. Lack of MGMT methylation in H3-K27M-gliomas correlates with temozolomide resistance; we previously reported imipridones ONC201/ONC206 reduce MGMT, EZH1 and EZH2 expression in H3-K27M-glioma cells. Divergent PDGFRA-mutations among MGMT-methylated versus unmethylated H3-G34R-gliomas warrants investigation of PDGFRA-signaling and epigenetic regulation. Our findings suggest divergent precision oncology therapeutic strategies to exploit unique vulnerabilities in H3-K27M and H3-G34R-gliomas.
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BibTeX
@misc{islam2026comparative,
title = {{Comparative Genomic and Epigenetic Landscape of Histone H3.3 G34R and K27M-Mutated Pediatric High-Grade Glioma Suggests Divergent Precision Oncology Strategies}},
author = {Z. Islam and L. Zhou and W. S. El-Deiry},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751433},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751433v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Comparative Genomic and Epigenetic Landscape of Histone H3.3 G34R and K27M-Mutated Pediatric High-Grade Glioma Suggests Divergent Precision Oncology Strategies
AU - Z. Islam
AU - L. Zhou
AU - W. S. El-Deiry
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751433
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751433v1
AB - Histone H3-G34R and H3-K27M mutations define distinct diffuse high-grade glioma subtypes diffuse hemispheric glioma (DHG), midline (DMG), and pontine gliomas (DIPG). We characterized pathway-architectures using cBioPortal and pedcBioPortal for H3-G34R (n=112) and H3-K27M (n=727) mutated-gliomas, co-mutations, copy numbers (CNA), and variant data (n=112/727, n=86/578, n=51/313). We evaluated altered-genes as oncogenic by OncoKB, Gene-Ontology (GO) heatmaps and process-enrichment using clusterProfiler (Benjamini-Hochberg-adjusted p<0.05). H3-G34R-gliomas harbored near-universal TP53 (94.1%), ATRX (81.4%) co-mutations and PDGFRA alteration (54.9% mutation; 17.1% amplification) within 4q12 amplicon that includes KIT and KDR. Pathway-enrichment converged on G1/S cell-cycle checkpoints, and epigenetic regulation, driven principally by TP53, ATRX, PTEN, BCOR, TERT, FBXW7, and PPM1D. CDK6 amplification was rare (2.6%), despite H3-G34R association with CDK6-dependency including benefit from CDK4/6 inhibition. H3-K27M-gliomas displayed PI3K/AKT pathway activation (PIK3CA, 14.9%; NF1, 13.3%; PDGFRA, 10.8%, PIK3R1, 7.8%; PTEN, 5.7%) and developmental signatures through NF1, PTEN, and SOX10 (4.95%) mutations. TP53 (62.2%) and ATRX (21.2%) co-mutations were less frequent in H3-K27M versus H3-G34R, while PPM1D was H3-K27M-enriched (19.3%). MGMT promoter methylation occurred frequently in H3-G34R (65.2%, 15/23) versus H3-K27M-gliomas (5.4%, 4/74), despite genome-hypomethylation of H3-G34R. H3-G34R-gliomas, unlike H3-K27M, upregulated ganglionic GSX2, DLX1, DLX2, and FOXG1. SOX10 was upregulated in H3-K27M-gliomas, versus H3-G34R. Lack of MGMT methylation in H3-K27M-gliomas correlates with temozolomide resistance; we previously reported imipridones ONC201/ONC206 reduce MGMT, EZH1 and EZH2 expression in H3-K27M-glioma cells. Divergent PDGFRA-mutations among MGMT-methylated versus unmethylated H3-G34R-gliomas warrants investigation of PDGFRA-signaling and epigenetic regulation. Our findings suggest divergent precision oncology therapeutic strategies to exploit unique vulnerabilities in H3-K27M and H3-G34R-gliomas.
ER -