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Some cases of glioblastoma caused by two fused genes
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The fusion of FGFR and TACC genes caused a small number of glioblastoma cases, but drugs that target the proteins produced by this synthesis can slow the growth of the lethal brain tumor, according to study data.
Affecting approximately 10,000 patients in the United States each year, glioblastomas are typically treated with surgery followed by radiation and chemotherapy.
The median survival is 14 months.
Considered a genetic aberration, the fusion of FGFR and TACC genes was found in just three of 97 tumors (3.1%) observed, according to researchers.
Still, oncogenic fusions are critical events in the pathogenesis of cancer, and researchers said the findings in the study are an important step in identifying treatable targets for the lethal brain tumor.
“Our research is doubly important,” Antonio Iavarone, MD, professor of pathology and neurology at Columbia University Medical Center, said in a press release. “From a clinical perspective, we have identified a druggable target for a brain cancer with a particularly dismal outcome. From a basic research perspective, we have found the first example of a tumor-initiating mutation that directly affects how cells divide, causing chromosomal instability. This discovery has implications for the understanding of glioblastoma as well as other types of solid tumors.”
Researchers examined cell abnormalities in glioblastomas by using parallel, paired-end sequencing of expressed transcripts to detect gene fusions in short-term cultures of glioma stem cells isolated from nine patients with glioblastoma.
Using a tool that detects split reads and inserts, researchers discovered six intrachromosomal rearrangements that stimulated in-frame fusion transcripts, most commonly the FGFR-TACC fusion.
“Although each gene plays a specific role in the cell, sometimes errors in the DNA cause two ordinary genes to fuse into a single entity,” said Raul Rabadan, PhD, assistant professor in the department of biomedical informatics in the Center for Computational Biology and Bioinformatics at the Columbia University College of Physicians and Surgeons.
Researchers analyzed the cell’s genomic material by examining pieces of glioblastoma genome from several samples and then extended their analysis to a larger set of glioblastomas provided by the Cancer Genome Atlas Project, according to Rabadan.
The protein produced by the FGFR-TACC fusion disrupted cellular division and displayed cancerous activity when introduced to astrocytes — cells that make up the brain’s supportive tissue.
“If this process happens incorrectly, you get uneven distribution of the chromosomes,” Iavarone said in a press release. “This condition, which is known as aneuploidy, is thought to be the hallmark of tumorigenesis.”
Researchers introduced FGFR-TACC into the brain cells of healthy mice. Aggressive brain tumors developed in 90% of the animals, confirming that gene fusion can lead to glioblastoma, they found.
Kinase inhibitors have been developed into effective treatment for patients whose tumors carry functional gene fusions, according to Iavarone and colleagues. Kinase inhibition of FGFR kinase corrected aneuploidy and oral administration of a FGFR inhibitor prolonged survival in mice with FGFR3-TACC3-initiated glioma.
“FGFR-TACC fusions could potentially identify a subset of glioblastoma patients who would benefit from targeted FGFR kinase inhibition,” the researchers concluded.
Disclosure: Drs. Iavarone and Rabadan received grants from NCI, National Library of Medicine and Partnership for Cure. For a full list of disclosures, please see the study.
Perspective
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David A. Reardon, MD
This work represents a significant finding. The major values here are threefold. First, it gives us a previously undefined genetic defect that is associated with the pathogenesis of some glioblastomas. The elegant work that was done along with the identification of this fusion transcript strongly implicates it as a pathogenetic factor driving development of some glioblastomas. Secondly, the mechanism of how this transcript leads to tumor development provides a more general area of future focus for identifying factors that may contribute to the development of glioblastoma. Specifically, the fusion transcript was translated to have a disrupting impact on mitosis and abnormal chromosomal number and structure. This one mechanism — although specific to a transcript found in only 3.1% of glioblastomas — nonetheless implicates an area of cancer cell biology that can now be evaluated with more detailed investigation for further insight into glioblastoma pathogenesis. Third and most importantly, we have another example of a specific genetic defect that may be exploited therapeutically to personalize cancer therapy. This finding suggests that there is a subset of patients where a specific biologically based therapeutic may be targeted for their specific tumor.Perspective
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Steven S. Rosenfeld, MD, PhD, MD, PhD
We have known for some time that glioblastomas are associated with a variety of oncogenic mutations. The elegant and very important study by Iavarone and colleagues adds a new type of mutation to this list, a fusion protein produced by an in-frame chromosomal translocation involving two known oncogenes — fibroblast growth factor receptor (FGFR) and transforming acidic coiled coil (TACC). This study shows that this fusion protein can be found in a small subset of glioblastomas where it may be the cause of the initial transforming event; that this mutation re-localizes the FGFR to the mitotic spindle poles, and in so doing, may contribute to the genetic instability found in these tumors. However, at this point, it may be a leap to argue on the basis of this study that we can now effectively treat the subset of patients with glioblastomas that contain this mutation (approximately 3.2%) with inhibitors of the FGF receptor.
It is not clear in patients who have already presented with a tumor whether the approach that works in the laboratory is going to work in the more realistic setting, because the genetic instability generated by a FGFR-TACC fusion event may lead over time to secondary, oncogenic mutations that no longer require the activity of FGFR. Furthermore, while the genetic background of the experimental systems used by these investigators in the laboratory were generally well defined, we know that the genetic background of patients with glioblastoma can be quite heterogeneous, and we do not yet know how this genetic variability would modulate patient responsiveness to such a therapeutic approach. These issues can only be resolved by conducting prospective clinical trials in patients screened for this mutation. Nevertheless, this is an extremely important study, as it provides a potential “roadmap” to a new approach to tailoring patient therapy by targeting one of the causative genetic lesions of glioblastoma.
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