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Neuro Oncol. 2018 Jan 10;20(1):123-131. doi: 10.1093/neuonc/nox149.

Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location.

Author information

1
Department of Pediatric and Adolescent Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
2
Department of Neuropathology, University Hospital Bonn, Bonn, Germany.
3
Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Goettingen, Germany.
4
Department of Child and Adolescent Health, University Medical Center Goettingen, Goettingen, Germany.
5
Department of Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany.
6
Department of Pediatrics, Schleswig-Holstein Medical University in Kiel, Kiel, Germany.
7
Department of Pediatrics, VU University Medical Center, Amsterdam, Netherlands.
8
Division of Oncology/Hematology, VU University Medical Center, Amsterdam, Netherlands.
9
Department of Pediatrics and Adolescent Medicine, University Hospital of Geneva, Geneva, Switzerland.
10
Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland.
11
Department of Pathology, Universitätsmedizin Greifswald, Greifswald, Germany.
12
Institute of Neuropathology, Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany.
13
Division of Pediatric Hematology and Oncology, Medical University Graz, Graz, Austria.
14
Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria.
15
Division of Pediatric Neurooncology, German Cancer Research Center Heidelberg, Heidelberg, Germany.
16
Department of Radiotherapy and Radiation Oncology, University of Leipzig Medical Center, Leipzig, Germany.

Abstract

Background:

The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis.

Methods:

Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection.

Results:

We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival.

Conclusion:

These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.

KEYWORDS:

K27M mutation; children; diffuse midline glioma; high-grade glioma; histone H3

PMID:
29016894
PMCID:
PMC5761525
DOI:
10.1093/neuonc/nox149
[Indexed for MEDLINE]
Free PMC Article

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