Detection of histone H3 K27M mutation and post-translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes
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Tina Huang2,*, Roxanna Garcia2,*, Jin Qi2, Rishi Lulla3, Craig Horbinski2,4, Amir Behdad4, Nitin Wadhwani5, Ali Shilatifard6, Charles James2,6 and Amanda M. Saratsis1,2
1Division of Pediatric Neurosurgery, Department of Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
2Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
3Division of Pediatric Hematology/Oncology, Hasbro Children's Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
5Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
6Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Amanda M. Saratsis, email: [email protected]
Keywords: diffuse midline glioma; pediatric glioma; diffuse intrinsic pontine glioma; histone H3K27M mutation; histone H3 post-translational modification
Received: August 10, 2018 Accepted: November 26, 2018 Published: December 14, 2018
Pediatric diffuse midline glioma is a highly morbid glial neoplasm that may arise in the thalamus or brainstem (also known as diffuse intrinsic pontine glioma or DIPG). Because tumor anatomic location precludes surgical resection, diagnosis and treatment is based on MR imaging and analysis of biopsy specimens. Up to 80% of pediatric diffuse midline gliomas harbor a histone H3 mutation resulting in the replacement of lysine 27 with methionine (K27M) in genes encoding histone H3 variant H3.3 (H3F3A) or H3.1 (HIST1H3B). H3K27M mutant glioma responds more poorly to treatment and is associated with worse clinical outcome than wild-type tumors, so mutation detection is now diagnostic for a new clinical entity, diffuse midline glioma H3K27M mutant, as defined in the most recent WHO classification system. We previously reported patterns of histone H3 trimethylation (H3K27me3) and acetylation (H3K27Ac) associated with H3K27M mutation that impact transcription regulation and contribute to tumorigenesis. Given the clinical implications of the H3K27M mutation and these associated H3 post-translational modifications (PTMs), we set to determine whether they can be characterized via immunohistochemistry (IHC) in a cohort of pediatric glioma (n = 69) and normal brain tissue (n = 4) specimens. We observed 100% concordance between tissue IHC and molecular sequencing for detecting H3K27M mutation. In turn, H3K37M and H3K27me3 results, but not H3K27Ac staining patterns, were predictive of clinical outcomes. Our results demonstrate H3K27M and H3K27me3 staining of pediatric glioma tissue may be useful for diagnosis, stratification to epigenetic targeted therapies, and longitudinal monitoring of treatment response.
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