The H3 K27M mutation has posed a devastating treatment challenge1-3
Dysregulation induced by H3 K27me3 loss in H3 K27M–mutant diffuse midline glioma may drive oncogenesis and contributes to poor patient prognosis3,4
The defining feature of H3 K27M–mutant diffuse midline glioma is H3 K27 trimethylation (H3 K27me3) loss4
H3 WILDTYPE
Normal trimethylation of 27th amino acid residue of histone H3 silences genes that are associated with oncogenesis.4
H3 K27M
H3 K27me3 loss disrupts gene silencing, leading to dysregulated gene expression and oncogenic expression and pathway activation.4
H3 K27me3 loss leads to epigenetic dysregulation and oncogenesis4
H3, histone 3; K, lysine; M, methionine; me, methyl.
There are significant challenges in the clinical management of H3 K27M–mutant diffuse glioma1-3
CNS WHO Grade 4 glioma5
The most aggressive form of glioma
Most frequently occurs in children and young adults, with a median age at diagnosis of 11 years, and impacts ~2000 patients annually1,6,7
Invariably lethal and rapid mortality1,6,8-10
Median overall survival is approximately 1 year from diagnosis and 5.1 months (95% CI: 3.9-7.7) from recurrence1,6,8-10
Surgical resection is typically not possible11
The tumor location makes surgical resection difficult and often not possible; resection does not confer a survival benefit over biopsy alone11-13
H3 K27M–mutant diffuse midline gliomas are typically unresectable. Radiation therapy remains the standard of care, but treatment options beyond radiation have been limited1-3
CI, confidence interval; CNS, central nervous system; WHO, World Health Organization.
References: 1. Vuong HG, Ngo TNM, Le HT, et al. Prognostic implication of patient age in H3K27M-mutant midline gliomas. Front Oncol. 2022;12:858148. doi:10.3389/fonc.2022.858148 2. van den Bent M, Saratsis AM, Geurts M, Franceschi E. H3 K27M-altered glioma and diffuse intrinsic pontine glioma: semi-systematic review of treatment landscape and future directions. Neuro Oncol. 2024;26(suppl 2):S110-S124. doi:10.1093/neuonc/noad220 3. Vallero SG, Bertero L, Morana G, et al. Pediatric diffuse midline glioma H3K27- altered: a complex clinical and biological landscape behind a neatly defined tumor type. Front Oncol. 2023;12:1082062. doi:10.3389/fonc.2022.1082062 4. Saratsis AM, Knowles T, Petrovic A, Nazarian J. H3K27M mutant glioma: disease definition and biological underpinnings. Neuro Oncol. 2024;26(suppl 2):S92-S100. doi:10.1093/neuonc/noad164 5. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251. doi:10.1093/neuonc/noab106 6. Zheng L, Gong J, Yu T, et al. Diffuse midline gliomas with histone H3 K27M mutation in adults and children: a retrospective series of 164 cases. Am J Surg Pathol. 2022;46(6):863-871. doi:10.1097/PAS.0000000000001897 7. Data on file: Chimerix, Inc. 8. Ostrom QT, Shoaf ML, Cioffi G, et al. National-level overall survival patterns for molecularly-defined diffuse glioma types in the United States. Neuro Oncol. 2023;25(4):799-807. doi:10.1093/neuonc/noac198 9. Mackay A, Burford A, Carvalho D, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell. 2017;32(4):520-537.e1-e5. doi:10.1016/j.ccell.2017.08.017 10. Bagley SJ, Umemura Y, Mendez JS, et al. Prognostic features of recurrent midline and H3 K27M-mutant glioma. Cancers. 2025;17(13):2107. doi:10.3390/cancers17132107 11. Ryba A, Özdemir Z, Nissimov N, et al. Insights from a multicenter study on adult H3 K27M-mutated glioma: surgical resection’s limited influence on overall survival, ATRX as molecular prognosticator. Neuro Oncol. 2024;26(8):1479-1493. doi:10.1093/neuonc/noae061 12. Hatoum R, Chen JS, Lavergne P, et al. Extent of tumor resection and survival in pediatric patients with high-grade gliomas: a systematic review and meta-analysis. JAMA Netw Open. 2022;5(8):e2226551. doi:10.1001/jamanetworkopen.2022.26551 13. Karremann M, Gielen GH, Hoffmann M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20(1):123-131. doi:10.1093/neuonc/nox149