Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults

Abstract

Background: "Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.

Methods: Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.

Results: Median patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus (n = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the H3F3A gene and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric DMGs. Accompanying mutations in TP53, PPM1D, FGFR1, NF1, and ATRX were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.

Conclusions: Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.

Keywords: H3 K27M; adult; diffuse midline glioma; genetics; survival.

Figure 1.

Patient demographics and tumor location for the 60 adults with DMG, H3 K27M-mutant: (A) Histogram shows the distribution of patient age at diagnosis, (B) sex and Karnofsky performance status at diagnosis, and (C) location of tumors.

Figure 2.

MRI radiologic features of H3 K27M-mutant DMGs in adults at the time of initial diagnosis. (A) Description of gadolinium enhancement on MRI of the 60 patients. (B) Post-gadolinium (B1) and FLAIR (B2) images from a non-enhancing tumor. A blood vessel courses through the left thalamic tumor (white arrowhead), and periventricular FLAIR hyperintensity indicates transependymal flow secondary to acute obstructive hydrocephalus (red arrowhead). (C) Several examples of DMGs with H3 K27M mutation with different enhancement patterns: nodular (C1), thin rim (C2), heterogeneous (C3), thick rim (C4), diffuse/solid enhancement (C5), and disseminated disease with a conus lesion and leptomeningeal spread (C6).

Figure 3.

Genetic profile of adult H3 K27M-mutant DMG. Summary plot of the next-generation sequencing results for the 21 evaluated patients, as well as immunohistochemical, FISH, and MGMT promoter methylation data for these tumors.

Figure 4.

Progression-free and overall survival in adults with DMG, H3 K27M-mutant. (A) Kaplan–Meier plot progression-free survival for all adult patients in this study. (B) Kaplan–Meier analysis of overall survival for adult patients in this study (“Adult DMG, H3.3 K27M”), compared to a previously published cohort of pediatric patients with diffuse gliomas with H3.3 K27M mutation located in any midline structure (“Pediatric DMG, H3.3 K27M”) and adult patients with IDH-wildtype GBM included in the TCGA study (“TCGA GBM IDH-WT”). (C) Kaplan–Meier analysis of overall survival of patients with thalamic H3.3 K27M-mutant diffuse gliomas, comparing adults in this study cohort to a previously published cohort of pediatric patients.