David Meredith, MD, PhD, is a neuropathologist at Brigham and Women’s Hospital. He received his MD/PhD dual degree from the University of Texas Southwestern Medical Center at Dallas and completed anatomic pathology and neuropathology training at Brigham and Women’s Hospital and Harvard Medical School. His clinical responsibilities include neuropathology, soft tissue pathology, and molecular diagnostics with specialization in the interpretation of next generation sequencing results in brain tumors.
David Mereditha, Catherine Gestrichb, Kristina Griecoa, Hart Lidovb, Keith Ligona, Sandro Santagataa, Kee Kiat Yeoc, Sanda Alexandrescub
aBrigham and Women’s Hospital, Boston, MA, USA; bBoston Children’s Hospital, Boston, MA, USA; cDana-Farber Cancer Institute, Boston, MA, USA
Large-scale sequencing efforts have identified co-occurring driver events, such as activating mutations in FGFR1 and BRAF, in occasional diffuse midline gliomas (DMGs) H3K27-altered, but their significance is incompletely explored. To better understand the clinicopathologic features of these tumors, we identified all H3K27-mutant gliomas from our internal sequencing database (2013-2021) of over 2,000 gliomas and collected detailed clinical information, pathologic features, mutational signatures, and copy number profiles for the resulting cohort.
We identified 77 patients (age range 2-68, median 26). The histologic diagnoses were DMG (n=55), anaplastic astrocytoma/glioblastoma (n=19), low-grade glioma (n=1), low-grade glioneuronal tumor (n=1), and ganglioglioma (n=1). Commonly recurring alterations were seen in TP53 (n=42), ATRX (n=17), NF1 (n=15), and PDGFRA (n = 4). Five cases had BRAF V600E (1 ganglioglioma; 4 DMG); 12 had FGFR1 N546K/D or K656E mutations (9 DMG; 3 anaplastic astrocytoma/glioblastoma). BRAF-mutant tumors most commonly arose in the brainstem, while FGFR1-mutant tumors were mostly located within the thalamus. Median overall survival for DMGs lacking BRAF or FGFR1 mutations was 12.9 months, while median survival for FGFR1-mutant gliomas was 14.2 months (p=0.186) and 22.5 months for BRAF-mutant tumors (p=0.285). Two patients with low-grade histology (ganglioglioma and low-grade glioneuronal tumor) were still alive at last follow-up (37 months and 78 months, respectively). Despite the failure to reach statistical significance, improved survival trends were observed for patients with secondary molecular drivers compared with conventional H3K27M DMG, especially in those with low-grade histology. These findings and the possibility of targeted therapy argue for comprehensive sequencing of H3K27-altered gliomas.