Near haploidization is a genomic hallmark which defines a molecular subgroup of giant cell glioblastoma

Abstract

Background: Giant cell glioblastoma (gcGBM) is a rare histologic subtype of glioblastoma characterized by numerous bizarre multinucleate giant cells and increased reticulin deposition. Compared with conventional isocitrate dehydrogenase (IDH)-wildtype glioblastomas, gcGBMs typically occur in younger patients and are generally associated with an improved prognosis. Although prior studies of gcGBMs have shown enrichment of genetic events, such as TP53 alterations, no defining aberrations have been identified. The aim of this study was to evaluate the genomic profile of gcGBMs to facilitate more accurate diagnosis and prognostication for this entity.

Methods: Through a multi-institutional collaborative effort, we characterized 10 gcGBMs by chromosome studies, single nucleotide polymorphism microarray analysis, and targeted next-generation sequencing. These tumors were subsequently compared to the genomic and epigenomic profile of glioblastomas described in The Cancer Genome Atlas (TCGA) dataset.

Results: Our analysis identified a specific pattern of genome-wide massive loss of heterozygosity (LOH) driven by near haploidization in a subset of glioblastomas with giant cell histology. We compared the genomic signature of these tumors against that of all glioblastomas in the TCGA dataset (n = 367) and confirmed that our cohort of gcGBMs demonstrated a significantly different genomic profile. Integrated genomic and histologic review of the TCGA cohort identified 3 additional gcGBMs with a near haploid genomic profile.

Conclusions: Massive LOH driven by haploidization represents a defining molecular hallmark of a subtype of gcGBM. This unusual mechanism of tumorigenesis provides a diagnostic genomic hallmark to evaluate in future cases, may explain reported differences in survival, and suggests new therapeutic vulnerabilities.

Keywords: giant cell glioblastoma; glioblastoma; loss of heterozygosity; near haploidization.

Figure 1.

Giant cell glioblastoma (gcGBM) demonstrates specific radiographic and histological features. (A) T2-weighted MRI of gcGBM in left frontal lobe demonstrating the circumscribed nature of the tumor. (B) H&E-stained tissue section of gcGBM demonstrating the high degree of tumor cell pleomorphism, along with the presence of giant and/or multinucleated tumor cells. (C) At lower magnification, many tumors are remarkably nodular and do not exhibit diffuse infiltration into adjacent normal brain tissue. (D) Dense perivascular and intratumoral lymphocytic inflammation is common in gcGBM. (E) Many tumors showed large regions of coagulative necrosis (dotted line indicates boundary between viable tumor on the left and infarcted tumor on the right). (F) Occasional tumors contained focal eosinophilic granular bodies (arrows). Scale bars = 25 µm in B and F, 50 µm in D and E, 100 µm in C.

Figure 2.

Near haploidization as a genomic hallmark of giant cell glioblastomas (gcGBMs). (A) Relative copy number landscape of gcGBMs. (B) Loss of heterozygosity (LOH) analysis of gcGBMs. (C) Stemline haploid clone identified by chromosome analysis of gcGBM7. (D) Doubled haploid clone detected in gcGBM7.

Figure 3.

Genomic characterization of giant cell glioblastomas (gcGBMs) versus The Cancer Genome Atlas (TCGA) GBMs. (A) Summary plot of copy number analysis across gcGBM (n = 10) cohort versus TCGA GBMs (n = 367). (B) Frequency of copy number aberration in gcGBMs versus TCGA GBMs (C) Density plot analysis of copy number size distribution of gcGBMs versus TCGA GBMs. (D) Genome-wide loss of heterozygosity analysis. (E) Frequency of mutations observed in gcGBM cohort. (F) Hierarchical clustering analysis of gcGBMs versus isocitrate dehydrogenase (IDH)-wildtype and IDH-mutated GBMs in the TCGA cohort.