Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas

Karisa C Schreck,Heather M Ames,Matthias Holdhoff,Nebojša Skorupan,Surabhi Ranjan,Charles G Eberhart,Chetan Bettegowda

doi:10.1007/s11060-019-03134-x

Abstract

PurposeH3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation.MethodsConsecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX.ResultsOf 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n = 18; 17.6 months) compared with high-grade wildtype tumors (n = 74; 7.7 months, p = 0.03).ConclusionsH3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.

Highlights

Diffuse midline gliomas are aggressive tumors, which were recently found to harbor a K27M mutation in HIST1H3B/C and H3F3A genes which code for mutant histone protein H3.1 and H3.3 respectively [1]
Extrapolating from the clinicopathologic features of diffuse intrinsic pontine gliomas (DIPGs) and the poor prognosis seen in pediatric diffuse midline gliomas with H3 K27M mutations, the presence of an H3 K27M mutation in an infiltrating astrocytoma of the midline automatically confers a grade IV status [2, 5]
One case showed both ATRX protein loss and H3 K27M mutation, while IDH1 R132H mutation was mutually exclusive with H3 K27M mutation in our dataset

Summary

Introduction

Diffuse midline gliomas are aggressive tumors, which were recently found to harbor a K27M mutation in HIST1H3B/C and H3F3A genes which code for mutant histone protein H3.1 and H3.3 respectively [1]. Journal of Neuro-Oncology (2019) 143:87–93 signature and clinical features, are recognized as a separate entity in the 2016 World Health Organization Classification of tumors of the central nervous system [2]. These tumors are found in midline locations such as the brainstem, thalamus, cerebellum and spinal cord, and are identified primarily in children. Extrapolating from the clinicopathologic features of DIPGs and the poor prognosis seen in pediatric diffuse midline gliomas with H3 K27M mutations, the presence of an H3 K27M mutation in an infiltrating astrocytoma of the midline automatically confers a grade IV status [2, 5]

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Conclusion