Posted: December 18, 2012
Researchers Use TCGA Glioblastoma Data in the Discovery of a Novel Fusion Gene Implicated in a Subset of Brain Tumors
Pritty Patel Joshi
Researchers at Columbia University Medical Center utilized glioblastoma multiforme (GBM) data from The Cancer Genome Atlas (TCGA) to identify and characterize a fusion gene present in some GBM tumors. GBM is a rapidly progressive, malignant brain cancer with limited therapeutic options. For a subset of patients, these findings hold promise for a significant breakthrough in the clinical management of this devastating disease.
Gene fusions result from chromosomal rearrangements known as translocations. These rearrangements describe the movement of DNA segments from one chromosome to another or to a new site on the same chromosome. Cancer researchers know that translocations can cause cancer by fusing two previously separate genes to create a new gene with oncogenic properties. Moreover, drugs that specifically target oncogenic fusion proteins have shown therapeutic success in the treatment of some cancers including leukemia and lung cancer.
Now, in a report published in a September 2012 issue of Science, a research team led by Antonio Iavarone, Ph.D. reveals that gene fusion events occur in the development of some GBMs. Their work identifies a promising new therapeutic target for this deadly brain cancer.
Characterization of a Novel Fusion Event between FGFR and TACC Genes in Glioblastomas
Dr. Iavarone and his colleagues developed a novel computational method called TX-Fuse to find gene fusions in GBM tumors. The scientists used this pipeline to analyze expression data derived from nine tumor samples. From these analyses, they identified six possible fusions.
The researchers then turned to the publicly available TCGA GBM dataset, which contains data from over 330 tumors, to determine the prevalence of the candidate fusions in GBM. They discovered that of the six candidates, fusions between the fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil 3 (TACC3) genes emerged as the only recurrent somatic genomic rearrangements in the TCGA dataset. Further analyses of an independent collection of GBMs showed that fusions involving FGFR3 and TACC3 or the related genes, FGFR1 and TACC1, were present in 3.1 percent of GBMs examined.
To determine if FGFR-TACC fusions could cause cells to form tumors, the scientists conducted a series of experiments in laboratory mice. They found that over 85 percent of mice expressing FGFR3-TACC3 in brain cells developed malignant tumors that were invasive, rapidly-growing, high-grade gliomas. These mice succumbed to their brain tumors within eight months. In follow-up experiments, the scientists demonstrated that treatment of mice harboring FGFR3-TACC3-induced gliomas with an FGFR inhibitor, AZD4547, could prolong their survival. These findings, the authors affirm, suggest that FGFR inhibitors should be tested in clinical trials in GBM patients whose tumors exhibit FGFR-TACC rearrangements.
Finally, the scientists explored how FGFR-TACC fusion genes could cause cancer. Using microscopes, they examined brain cells undergoing cell division to produce ‘daughter’ cells. They discovered that compared to control cells, which did not express FGFR-TACC fusions, FGFR3-TACC3- or FGFR1-TACC1-expressing cells produced a higher fraction of daughter cells exhibiting aneuploidy, a type of chromosomal abnormality where cells have extra or missing chromosomes. In light of these findings, the authors propose that chromosomal instability, a hallmark of cancer, may result from a single tumor-initiating event such as the oncogenic fusion of the FGFR and TACC genes.
Targeting Oncogenic Fusion Proteins in Glioblastomas
The researchers in this study sought to identify oncogenic gene fusions implicated in the development of GBM tumors. Their identification of FGFR-TACC fusions provides the first example of a dominant mutation liable for aneuploidy in human cancer. These results not only offer scientists a better understanding of how chromosomal instability occurs in tumors but also reveal a novel therapeutic target for some individuals with GBM.
Notably, FGFR-TACC fusions were found in 3.1 percent of tumors examined suggesting that any therapy based on these rearrangements would only benefit a small subset of patients with GBM. Future analyses of TCGA data could facilitate the identification and characterization of additional oncogenic fusion genes that might be present in GBM or other tumor types. Such analyses could accelerate the development of precision therapies for many cancers.
Singh D., Chan J.M., Zoppli P., Niola F., Sullivan R., Castano A., Liu EM., Reichel J., Porrati P., Pellegatta S., et al. (2012) Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma. Science. 337(6099):1231-5. Read the full article.