Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions

Mata, Douglas A.; Benhamida, Jamal; Lin, Andrew; Vanderbilt, Chad; Yang, Soo‐Ryum; Villafania, Liliana; Ferguson, Donna C.; Jonsson, Philip; Miller, Alexandra; Tabar, Viviane; Brennan, Cameron; Moss, Nelson S.; Sill, Martin; Benayed, Ryma; Mellinghoff, Ingo K.; Rosenblum, Marc K.; Arcila, Maria E.; Ladanyi, Marc; Bale, Tejus

doi:10.1186/s40478-020-01058-6

Cited by 30 publications

(30 citation statements)

References 42 publications

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“…More recently, targeting fusion transcripts has expanded into other cancer types. These include the application of inhibitors of ALK-containing fusions in lung cancers [178] and anaplastic large-cell lymphomas [169], NTRK-containing fusions in various solid tumours [179][180][181], and FCGR-TACC fusions in glioblastoma [182,183] and other malignancies [184]. However, the utility of SVs as therapeutic targets is not limited to gene fusions.…”

Section: The Evolutionary and Clinical Impacts Of Structural Variants...mentioning

confidence: 99%

Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

Hamdan

Ewing

2022

The Journal of Pathology

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Structural variants (SVs) represent a major source of aberration in tumour genomes. Given the diversity in the size and type of SVs present in tumours, the accurate detection and interpretation of SVs in tumours is challenging. New classes of complex structural events in tumours are discovered frequently, and the definitions of the genomic consequences of complex events are constantly being refined. Detailed analyses of short-read whole-genome sequencing (WGS) data from large tumour cohorts facilitate the interrogation of SVs at orders of magnitude greater scale and depth. However, the inherent technical limitations of short-read WGS prevent us from accurately detecting and investigating the impact of all the SVs present in tumours. The expanded use of long-read WGS will be critical for improving the accuracy of SV detection, and in fully resolving complex SV events, both of which are crucial for determining the impact of SVs on tumour progression and clinical outcome. Despite the present limitations, we demonstrate that SVs play an important role in tumourigenesis. In particular, SVs contribute significantly to late-stage tumour development and to intratumoural heterogeneity. The evolutionary trajectories of SVs represent a window into the clonal dynamics in tumours, a comprehensive understanding of which will be vital for influencing patient outcomes in the future. Recent findings have highlighted many clinical applications of SVs in cancer, from early detection to biomarkers for treatment response and prognosis. As the methods to detect and interpret SVs improve, elucidating the full breadth of the complex SV landscape and determining how these events modulate tumour evolution will improve our understanding of cancer biology and our ability to capitalise on the utility of SVs in the clinical management of cancer patients.

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Section: The Evolutionary and Clinical Impacts Of Structural Variants...mentioning

confidence: 99%

Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

Hamdan

Ewing

2022

The Journal of Pathology

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“…The RNA sequencing of recurrent GBM revealed the presence of FGFR3 exon17- TACC3 exon 10 (Catalog of Somatic Mutations in Cancer mutation identifier COSF1434) fusion ( Figure 3 ). Moreover, NGS sequencing identified the presence of the most common mutations associated with FGFR3-TACC3 fusion in GBM, IDH wt: the pathogenic deletion on the PTEN gene (p.Trp111Ter) and TERT c.C228T promoter mutation ( 16 ). Furthermore, chromosome 10q loss without chromosome seven gain was detected, while no EGFR, MDM2 , and CDK4 amplification nor CDKN2A homozygous deletion were found in the analyzed sample.…”

Section: Case Presentationmentioning

confidence: 99%

Glioblastoma, IDH-Wild Type With FGFR3-TACC3 Fusion: When Morphology May Reliably Predict the Molecular Profile of a Tumor. A Case Report and Literature Review

Broggi

Piombino²,

Altieri

et al. 2022

Front. Neurol.

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It has been reported that in-frame FGFR3-TACC3 fusions confer to glioblastomas, IDH-wild type (GBMs, IDHwt) some unusual morphologic features, including monomorphous rounded cells with ovoid nuclei, nuclear palisading, endocrinoid network of “chicken-wire” vessels, microcalcifications and desmoplastic stroma, whose observation may predict the molecular profile of the tumor. We herein present a case of recurrent GBMs, IDHwt, exhibiting some of the above-mentioned morphological features and a molecularly-proven FGFR3-TACC3 fusion. A 56-year-old man presented to our hospital for a recurrent GBM, IDHwt, surgically treated at another center. Histologically, the tumor, in addition to the conventional GBM morphology, exhibited the following peculiar morphologic features: (1) monomorphous neoplastic cells with rounded nuclei and scant pale cytoplasm; (2) thin capillary-like vessels with “chicken-wire” pattern; (3) nuclear palisading; (4) formation of vague perivascular pseudorosettes; (5) spindled tumor cells embedded in a loose, myxoid background. Based on this unusual morphology, molecular analyses were performed and an FGFR3 exon17-TACC3 exon 10 fusion was found. The present case contributes to widening the morphologic spectrum of FGFR3-TACC3-fused GBM, IDHwt and emphasizes that pathologists, in the presence of a GBM, IDHwt with unconventional morphology, should promptly search for this fusion gene.

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“…Fusion of the fibroblast growth receptor 3 (FGFR3) gene to the transforming acidic coiled coil containing the protein 3 (TACC3) gene leads to formation of the FGFR3-TACC3 fusion gene. The hybrid gene codes for one of the most recurrent oncogenic fusion proteins and can be found in about 3% of squamous NSCLC and urothelial carcinoma, 3.9% of cervical cancer patients, and in 4% of glioblastoma patients [ 39 , 42 , 59 , 60 ]. A FGFR3-BAIAP2L1 fusion was also found in bladder and lung cancer [ 22 , 61 ].…”

Section: Fgfr-fusions In Cancermentioning

confidence: 99%

FGFR3-TACCs3 Fusions and Their Clinical Relevance in Human Glioblastoma

Gött

Uhl

2022

IJMS

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Oncogenic fusion genes have emerged as successful targets in several malignancies, such as chronic myeloid leukemia and lung cancer. Fusion of the fibroblast growth receptor 3 and the transforming acidic coiled coil containing protein—FGFR3-TACC3 fusion—is prevalent in 3–4% of human glioblastoma. The fusion protein leads to the constitutively activated kinase signaling of FGFR3 and thereby promotes cell proliferation and tumor progression. The subgroup of FGFR3-TACC3 fusion-positive glioblastomas presents with recurrent clinical and histomolecular characteristics, defining a distinctive subtype of IDH-wildtype glioblastoma. This review aims to provide an overview of the available literature on FGFR3-TACC3 fusions in glioblastoma and possible implications for actual clinical practice.

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Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions

Cited by 30 publications

References 42 publications

Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

Glioblastoma, IDH-Wild Type With FGFR3-TACC3 Fusion: When Morphology May Reliably Predict the Molecular Profile of a Tumor. A Case Report and Literature Review

FGFR3-TACCs3 Fusions and Their Clinical Relevance in Human Glioblastoma

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