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 three 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.

“De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade

“…The latter two genes ( PTEN and NF1 ) were frequently inactivated in the de novo RRD glioblastomas through short somatic variants as described above, but larger gene deletions were not present in this tumor cohort. Also notably, two of the nine (22%) de novo RRD glioblastomas (patients #2 and #9) demonstrated near genomic haploidization and subsequent reduplication of most chromosomes in the genome, as was recently reported in a unique molecular subset of giant cell glioblastomas [ 4 ]. This near genomic haploidization may likely have served as the tumor-initiating event by eliminating the remaining MSH6 wildtype allele, thereby resulting in the mismatch repair deficiency that led to accumulation of mutations in oncogenes and tumor suppressor genes that drove tumor development.…”

IDH-wild type glioblastomas featuring at least 30% giant cells are characterized by frequent RB1 and NF1 alterations and hypermutation

“…It is still unclear whether GC-GBM represents a distinct entity or only a morphological variant of IDH -wt GBM. Most of our current knowledge on its genetic features comes from few available molecular studies, mainly focusing on the analysis of selected genetic anomalies [ 6 – 11 ]. According to these, GC-GBM seems to be a hybrid between IDH -wt and IDH -mutant GBM.…”

“…According to these, GC-GBM seems to be a hybrid between IDH -wt and IDH -mutant GBM. Similarly to the former, it has a high prevalence of PTEN mutations (18/58 cases, 31%), but alike the latter, it also shows a high incidence of TP53 mutations (73/83 cases, 88%), low frequency of EGFR amplification (10/89 cases; 11%) and of TERT promoter mutations (21/65, 32%) [ 6 – 11 ]. Only one study performed a comprehensive molecular profiling of 10 GC-GBMs by whole exome sequencing [ 10 ].…”

2021 World Health Organization Classification of Brain Tumors

“…18 Giant cell glioblastomas, characterized by frequent multinucleated tumor cells with expansive cytoplasm, show enrichment in TP53 variations and frequent near-haploidy. 19 In addition, these tumors may demonstrate mismatch repair deficiencies and should be evaluated for mismatch repairrelated proteins by performing immunohistochemistry for MLH1, MSH2, MSH6, and PMS2.…”