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. 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

Michael Karremann  1 , Gerrit H Gielen  2 , Marion Hoffmann  3   4 , Maria Wiese  3   4 , Niclas Colditz  3   4 , Monika Warmuth-Metz  5 , Brigitte Bison  5 , Alexander Claviez  6 , Dannis G van Vuurden  7   8 , André O von Bueren  3   4   9   10 , Marco Gessi  2 , Ingrid Kühnle  3   4 , Volkmar H Hans  11   12 , Martin Benesch  13   14 , Dominik Sturm  15 , Rolf-Dieter Kortmann  16 , Andreas Waha  2 , Torsten Pietsch  2 , Christof M Kramm  3   4
Affiliations

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

Michael Karremann et al. Neuro Oncol. .

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.

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Figures

Fig. 1
Fig. 1
Distribution of H3 K27 mutational status in 85 pediatric patients (including 8 children <3 y of age) with diffuse midline glioma.
Fig. 2
Fig. 2
(A) OS in 76 pediatric patients >3 y of age with diffuse midline gliomas, compared by H3 K27 mutational status (*survival data were missing for one patient). (B) OS comparing H3 K27M-mutant gliomas to only H3 K27-wildtype glioblastoma WHO grade IV.
Fig. 3
Fig. 3
OS in 61 patients >3 years of age at diagnosis with H3 K27M-mutant diffuse midline gliomas according to anatomic tumor location.
Fig. 4
Fig. 4
OS in 56 patients with H3 K27M-mutant diffuse midline gliomas (DMGIV) according to histopathological tumor grading (eg, WHO grade III vs WHO grade IV).
Fig. 5
Fig. 5
(A) Extent of tumor resection was not associated with improved survival in H3 K27M-mutant midline glioma (DMGIV). (B) In contrast, there was a trend to an improved survival in H3 K27-wildtype HGG with extended resection.
See this image and copyright information in PMC

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