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

Abstract

Purpose H3 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. Methods Consecutive 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. Results Of 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). Conclusions H3 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.

A case of diffuse midline glioma, H3 K27M mutant mimicking a hemispheric malignant glioma in an elderly patient

“…13,14 Elderly onset DMG is therefore not extremely rare, the H3 status of a hemispheric diffuse glioma affecting the midline should be confirmed pathologically even in an elderly patient. Generally, hemispheric diffuse gliomas arising in elderly patients are commonly determined to be IDH wild-type glioblastomas (GBMs).…”

“…In the case series by Solomon et al, two of the adults with DMG, H3 K27M mutant (N = 19) were over 60 years old (10.5%) and in the series by Schreck et al on adult DMG, H3 K27M mutant (N = 18) three patients over 60 years were included (16.7%). 13,14 Elderly onset DMG is therefore not extremely rare, the H3 status of a hemispheric diffuse glioma affecting the midline should be confirmed pathologically even in an elderly patient.…”

Clinical efficacy and predictive biomarkers of ONC201 in H3 K27M-mutant diffuse midline glioma

“…The histone mutation H3 K27M in diffuse midline gliomas (DMG) is associated with aggressive clinical behavior and overall median survival of 12.0 months [1][2][3] . The H3 K27M mutation is most commonly found in midline central nervous system (CNS) structures in children and young adults 4 , where the thalamus and brainstem account for the majority of patients carrying the mutation 1,[5][6][7] . We assessed the bloodbrain barrier (BBB) penetration of ONC201 in midline brain structures in non-tumor bearing mice.…”

Molecular genetic features of pediatric gliomas

“…Долгое время мутация K27M в гене H3F3A считалась патогномоничной для срединных HGG у детей. За последние несколько лет ряд исследовательских групп отметил, что и у взрослых пациентов с глиомами срединной локализации возможно наличие мутации H3 K27M [33][34][35]. Так, K.C.…”

“…Schreck и соавт. сообщают о наличии H3 K27M в 15% случаев HGG (18/123), соответствующих диагностическим критериям термина ВОЗ «диффузная срединная глиома» у взрослых пациентов в возрасте 19-86 лет (медиана -51 год) [33]. А. Ebrahimi и соавт.…”