A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4

Abstract

Malignant brain tumors, known as H3K27-altered diffuse midline glioma (DMG) and H3G34-mutant diffuse hemispheric glioma (DHG), can affect individuals of all ages and are classified as CNS WHO grade 4. We comprehensively characterized 390 H3F3A-mutant diffuse gliomas (201 females, 189 males) arising in pediatric patients (under 20 years old) and adults (20 years and older) evaluated by the CGP program at Foundation Medicine between 2013 and 2020. We assessed information from pathology reports, histopathology review, and clinical data. The cohort included 304 H3K27M-mutant DMG (156 females, 148 males) and 86 H3G34-mutant DHG (45 females, 41 males). Median patient age was 20 years (1-74 years). The frequency of H3K27M-mutant DMG was similar in both pediatric and adult patients in our cohort-48.6% of the patients were over 20 years old, 31.5% over 30, and 18% over 40 at initial diagnosis. FGFR1 hotspot point mutations (N546K and K656E) were exclusively identified in H3K27M-mutant DMG tumors (64/304, 21%; p = 0.0001); these tend to occur in older patients (median age: 32.5 years) and mainly arose in the diencephalon. H3K27M-mutant DMG had higher rates of mutations in NF1 (31.0 vs 8.1%; p = 0.0001) and PIK3CA/PIK3R1 (27.9% vs 15.1%; p = 0.016) compared to H3G34-mutant DHG. However, H3G34-mutant DHG had higher rates of targetable alterations in cell-cycle pathway genes (CDK4 and CDK6 amplification; CDKN2A/B deletion) (27.0 vs 9.0%). Potentially targetable PDGFRA alterations were identified in ~ 20% of both H3G34-mutant DHG and H3K27M-mutant DMG. Overall, in the present study H3K27M-mutant DMG occurred at similar rates in both adult and patient patients. Through our analysis, we were able to identify molecular features characteristic of DMG and DHG. By identifying the recurrent co-mutations including actionable FGFR1 point mutations found in nearly one-third of H3K27M-mutant DMG in young adults, our findings can inform clinical translational studies, patient diagnosis, and clinical trial design.

Keywords: Astrocytoma; Brain neoplasms; Brain stem neoplasms; CDKN2A; Central nervous system neoplasms; Diffuse intrinsic pontine glioma; FGFR1; Genetics; Genomics; Glioblastoma; Glioma; H3F3A; Infratentorial neoplasms; Molecular pathology; Neuroepithelial neoplasms; Neuropathology; PDGFRA; Supratentorial neoplasms.

Fig. 1

Age and sex distribution of 390 patients with H3F3A-mutant gliomas including a 304 with H3K27M-mutant Diffuse Midline Glioma and b 86 with H3G34-mutant Diffuse Hemispheric Glioma

Fig. 2

Comparison of recurrent genomic alterations between 304 patients with H3 K27M-mutant Diffuse Midline Glioma, and 86 H3 G34-altered Diffuse Hemispheric Glioma

Fig. 3

Mutation spectrum of 390 patients with H3F3A-mutant gliomas. a Mutation spectrum of all 304 patients with H3K27M DMG. b Mutation spectrum of 156 patients < 20 years with H3K27M DMG. c Mutation profile of 86 patients with H3G34-mutant DHG. d Mutation spectrum of 148 patients ≥ 20 years with H3K27M DMG. Cell cycle category includes CDK4/6 amplification and CDKN2A/B deletions

Fig. 4

Mutation spectrum in H3K27M-mutant DMG with co-occurring mutations in FGFR1. Loc: location, ST supratentorial