{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Brown University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "Z. Islam"
    },
    {
      "name": "L. Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "W. S. El-Deiry"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/abr8bwkca5aax.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.14.751433",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.14.751433v1.full",
  "id": "abr8bwkca5aax",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.14.751433v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2716|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7213462542",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.14.751433v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/abr8bwkca5aax.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:43Z",
      "native_id": "10.64898/2026.09.14.751433",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.14.751433v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Comparative Genomic and Epigenetic Landscape of Histone H3.3 G34R and K27M-Mutated Pediatric High-Grade Glioma Suggests Divergent Precision Oncology Strategies",
  "title_text": "Comparative Genomic and Epigenetic Landscape of Histone H3.3 G34R and K27M-Mutated Pediatric High-Grade Glioma Suggests Divergent Precision Oncology Strategies",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:43Z",
  "url": "https://research.draconitic.com/paper/abr8bwkca5aax",
  "venue": "bioRxiv",
  "versions": []
}