Integrated high‐resolution copy number and histomolecular analysis of diffuse hemispheric glioma, H3 G34 ‐mutant reveals universal TP53 abnormalities

Year: 2026

Type: article

Abstract: Diffuse hemispheric glioma, H3 G34-mutant (DHG-H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high-resolution copy number profiling of a series of 60 DHG-H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187-gene mutation and fusion targeted neuro-oncology next-generation sequencing panel (n = 60) and Oncoscan chromosomal microarray (n = 26) by a single laboratory (2018-2022). A subset of cases had immunohistochemical results for OLIG2 (n = 42), p53 (n = 48), and ATRX (n = 46), and methylation array data (n = 8). Median age at testing was 21 years (range, 12-50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3-3A G34 mutations included G34R (n = 56; 94%), G34V (n = 3), and a non-canonical G34E (n = 1). Concurrent mutations most often involved TP53 (n = 55; 92%), ATRX (n = 50; 83%), and PDGFRA (n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy-neutral loss of heterozygosity (cnLOH) encompassing TP53. This copy number profile was reminiscent of that seen in Grade 4 IDH-mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high-resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG-H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH-a copy number abnormality that has been largely unrecognized-for this new 2021 World Health Organization central nervous system tumor type.

Source: Brain Pathology

DOI: 10.1111/bpa.70076

Institutions: Mayo Clinic, Orlando Regional Medical Center, University of Virginia Health System, University of Oklahoma Health Sciences Center, Houston Methodist, Children's National, Corewell Health, National Cancer Institute, Center for Cancer Research

Language: English

Topic: Glioma Diagnosis and Treatment

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,080

OpenAlex ID: W7127998166