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

Barresi, Valeria; Simbolo, Michele; Mafficini, Andrea; Martini, Maurizio; Calicchia, Martina; Piredda, Maria Liliana; Ciaparrone, Chiara; Bonizzato, Giada; Ammendola, Serena; Caffo, Maria; Pinna, Giampietro; Sala, Francesco; Lawlor, Rita T.; Ghimenton, Claudio; Scarpa, Aldo

doi:10.1186/s40478-021-01304-5

Cited by 10 publications

(20 citation statements)

References 49 publications

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“…8 We recently found that, above the high frequency of TP53 mutations, GBMs histologically featuring at least 30% giant cells (GCs) display a significantly higher rate (25.6%) of RB1 alterations than conventional GBMs (9.4%). 5 This finding, also reported by other authors, 9 suggests that the alteration of RB1 could be a further distinctive feature of GBMs with GCs.…”

Section: Introductionsupporting

confidence: 69%

“…5,12 In a subset of cases (42GL-71GL), the results were confirmed using the SureSelectXT HS CD Glasgow Cancer Core assay (Agilent Technologies, Santa Clara, CA, USA). 5 In the remaining five GBMs with GCs and eight PXAs (cases 1X-14X), we used the Oncomine Tumour Mutational Load (TML) panel (Thermo Fisher) to assess the mutations and CNV of 409 cancer-related genes.…”

Section: E T H I C Smentioning

confidence: 82%

“…In 32 GBMs with GCs (cases 1GL, 5GL, 9GL, and 42GL–71GL), we had already assessed tumour mutational burden (TMB), mutations, and copy number variations (CNV) of 409 cancer‐related genes using the targeted NGS panel Oncomine Tumour Mutational Load (TML) (Thermo Fisher, Waltham, MA, USA), which covers 1.65 Mb of genomic space 5,12 . In a subset of cases (42GL–71GL), the results were confirmed using the SureSelectXT HS CD Glasgow Cancer Core assay (Agilent Technologies, Santa Clara, CA, USA) 5 …”

Section: Methodsmentioning

confidence: 96%

“…A pathologist (V.B.) revised the histological slides of all cases, to assess the presence of eosinophilic granular bodies (EGB), lymphocytic infiltrate, and spindle cells to establish the histological grade of PXA according to the criteria of the 5th edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumours, 13 and to quantify the percentage of GCs in GBMs 5 . A representative paraffin block was selected for the immunohistochemical, fluorescence in situ hybridisation (FISH) and molecular (in cases 1X to 14X) analyses.…”

Section: Methodsmentioning

confidence: 99%

“…This is a subtype of GBM that features a gross circumscription, and is histologically characterized by multinucleated giant cells in a background of small, often fusiform cells, and lymphocytic infiltrate 4 . The molecular landscape of giant‐cell GBM is dominated by impairment of the TP53/MDM2 and PTEN/PI3K pathways 5 . Thus, strong and diffuse p53 immunostaining favours giant‐cell GBM in the differential diagnosis of PXA 6 .…”

Section: Introductionmentioning

confidence: 99%

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pRB immunostaining in the differential diagnosis between pleomorphic xanthoastrocytoma and glioblastoma with giant cells

et al. 2022

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Aims Pleomorphic xanthoastrocytoma (PXA) is a rare circumscribed glioma, characterized by frequent BRAF p. V600E mutation, and classified as grade 2 or 3. Owing to overlapping clinical–pathological features, the histological distinction from glioblastoma (GBM) with giant cells (GCs) is challenging. Based on the high frequency of TP53 and RB1 alterations in the latter, this study aimed to assess the value of BRAF, p53, and pRB immunostainings in the differential diagnosis. Methods and results In 37 GBMs with ≥30% GCs and in eight PXAs, we assessed the alterations of 409 cancer‐related genes and immunostainings for BRAF, p53, and pRB. GBMs with GCs were TP53‐mutated in 30 cases, RB1‐altered in 11, and BRAF‐mutated in none. PXAs were BRAF‐mutated in six cases, TP53‐mutated in three, and RB1‐altered in none. pRb immunostaining was lost in 25 GBMs (11 RB1‐altered and 14 RB1‐unaltered), retained in all PXAs and six GBMs, and inconclusive in six GBMs. pRb loss had 100% specificity and 80.6% sensitivity for GBM with GCs. P53 immunostaining was observed in 22 TP53‐mutated GBMs and in one TP53‐mutated PXA. It showed 87.5% specificity and 60% sensitivity to identify GBM with GCs. BRAF immunostaining corresponded to BRAF mutation status and it had 100% specificity and 75% sensitivity for detecting PXA. Conclusion This study shows for the first time that loss of pRB immunostaining is sensitive and specific for distinguishing GBM with GCs from PXA in routine practice. Thus, it could complement an immunohistochemical panel that includes BRAF and p53 immunostainings for the differential diagnosis.

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Section: Introductionsupporting

confidence: 69%

Section: E T H I C Smentioning

confidence: 82%

Section: Methodsmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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pRB immunostaining in the differential diagnosis between pleomorphic xanthoastrocytoma and glioblastoma with giant cells

et al. 2022

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

Hadad,

Gupta,

Oberheim Bush

et al. 2023

Acta Neuropathol

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Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant “ultrahypermutation”. The median age at diagnosis was 50 years (range 27–78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as “Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A”. Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that “De novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

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hGFAP-mediated GLI2 overexpression leads to early death and severe cerebellar malformations with rare tumor formation

Niesen¹,

Hermans‐Borgmeyer²,

Krüger³

et al. 2023

iScience

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

Cited by 10 publications

References 49 publications

pRB immunostaining in the differential diagnosis between pleomorphic xanthoastrocytoma and glioblastoma with giant cells

pRB immunostaining in the differential diagnosis between pleomorphic xanthoastrocytoma and glioblastoma with giant cells

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

hGFAP-mediated GLI2 overexpression leads to early death and severe cerebellar malformations with rare tumor formation

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