Stylized GLIOMA hero with a brain image as the O indicating the importance of testing for H3 K27M mutation in all diffuse gliomas Stylized GLIOMA hero with a brain image as the O indicating the importance of testing for H3 K27M mutation in all diffuse gliomas

About H3 K27M

The H3 K27M mutation is associated with poor prognosis in diffuse gliomas1-3

H3 K27M–mutant diffuse gliomas can occur across the brain, in both midline and non-midline structures, and are characterized by the global loss of H3 K27 trimethylation (H3 K27me3 loss).4

Image of the brain showing the importance of identifying mutations through imaging, biopsy, and other methods
Non-midline structures Midline structures

Molecular and cellular changes arising from the H3 K27M mutation5,6

Flow chart of molecular and cellular changes driven by H3 K27M mutation, specifically histone trimethylation loss and downstream effects Flow chart of molecular and cellular changes driven by H3 K27M mutation, specifically histone trimethylation loss and downstream effects
H3 K27me3 loss4,7
  • Disrupts epigenetic pathways
  • Results in activation of oncogenic pathways
  • Leads to a cascade of events that results in diffuse gliomas with a poor prognosis

Historically, survival rarely exceeds 2 years
from diagnosis in patients with H3 K27M–mutant diffuse gliomas1-3

The World Health Organization classifies diffuse gliomas with an H3 K27M mutation as Grade 4 irrespective of diffuse glioma histology.8-10

The Need for Biopsy

Brain tumor biopsy can
unlock crucial insights11,12

The decision to biopsy is a critical step when
managing gliomas11,12

While there is always surgical risk, modern advancements in image-guided stereotactic biopsy have enhanced access to midline tumors and improved biopsy safety.4,12

With these improvements, studies of thalamic and brain stem biopsies now show12:

<6% risk

of transient neurological damage

~1% risk

of permanent
disability

Image of the brain showing the importance of identifying mutations through imaging, biopsy, and other methods

When imaging raises questions, biopsy and molecular testing provide answers.7,11,12

IHC and NGS Testing

Early molecular testing is essential for proper diagnosis11,12

Make informed disease-management decisions by identifying mutations as soon as possible11,12

Imaging alone cannot confirm mutational status—a biopsy with subsequent immunohistochemistry (IHC) or next-generation sequencing (NGS) reveals specific mutations, such as H3 K27M, that can inform and help optimize disease management.7,11,12

IHC

IHC is widely accessible and highly sensitive for identifying H3 K27 variants as it uses antibodies specific to H3 K27M and H3 K27me37,13,14

NGS

NGS can detect a broad range of genomic alterations to identify specific mutations and potential therapeutic targets7,15

Both techniques are standard practice for the accurate diagnosis of gliomas and provide additional data to help tailor treatment plans.4,15

Management Methods

Treating H3 K27M–mutant diffuse gliomas is challenging7,16

Historically, there have been no effective systemic therapies that target H3 K27M–mutant diffuse gliomas, leaving clinicians and patients in a difficult position.7,16

H3 K27M–mutant diffuse gliomas are frequently found in midline structures, making them difficult to resect16
The existing standard of care is radiation therapy—however, median overall survival is approximately 1 year post diagnosis1-3,7,16
The lack of effective systemic treatments in the post-radiation treatment setting represents a significant unmet need1-3,7,16

Stay Informed

Test every glioma for H3 K27M as early as possible

Identifying an H3 K27M mutation can help inform prognosis and clinical management. Now, with advances in testing techniques, determining mutational status is more attainable, and more important, than ever before.4,11,12,15

Get the latest on H3 K27M–mutant diffuse glioma developments

Stylized GLIOMA hero with a brain image as the O indicating the importance of testing for H3 K27M mutation in all diffuse gliomas Stylized GLIOMA hero with a brain image as the O indicating the importance of testing for H3 K27M mutation in all diffuse gliomas
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. 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 3. 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 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. Al Sharie S, Abu Laban D, Al-Hussaini M. Decoding diffuse midline gliomas: a comprehensive review of pathogenesis, diagnosis and treatment. Cancers (Basel). 2023;15(19):4869. doi:10.3390/cancers15194869 6. Lowe BR, Maxham LA, Hamey JJ, Wilkins MR, Partridge JF. Histone H3 mutations: an updated view of their role in chromatin deregulation and cancer. Cancers (Basel). 2019;11(5):660. doi:10.3390/cancers11050660 7. 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 8. 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 9. Louis DN, Giannini C, Capper D, et al. cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol. 2018;135(4):639-642. doi:10.1007/s00401-018-1826-y 10. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820. doi:10.1007/s00401-016-1545-1 11. Meyronet D, Esteban-Mader M, Bonnet C, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol. 2017;19(8):1127-1134. doi:10.1093/neuonc/now274 12. Sheikh SR, Patel NJ, Recinos VMR. Safety and technical efficacy of pediatric brainstem biopsies: an updated meta-analysis of 1000+ children. World Neurosurg. 2024;189:428-438. doi:10.1016/j.wneu.2024.06.163 13. Penkova A, Kuziakova O, Gulaia V, et al. Comprehensive clinical assays for molecular diagnostics of gliomas: the current state and future prospects. Front Mol Biosci. 2023;10:1216102. doi:10.3389/fmolb.2023.1216102 14. 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 15. Kim T, Lee A, Ahn S, Park JS, Jeun SS, Lee YS. Comprehensive molecular genetic analysis in glioma patients by next generation sequencing. Brain Tumor Res Treat. 2024;12(1):23-39. doi:10.14791/btrt.2023.0036 16. 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