Study Identifies Common Driver of a Childhood Brain Tumor


Key Points

  • Researchers found that 70% of young patients with ependymomas in the front part of the brain carried an alteration that fuses RELA with the C11orf95 gene.
  • In mouse models, this translocation produces abnormal proteins that rapidly caused fatal brain tumors.
  • The study demonstrates that a frequent mutation in the NF-κB pathway is sufficient to transform normal brain cells into cancer cells and drive tumor development.

The St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project has identified the most common genetic alteration ever reported in the brain tumor ependymoma and evidence that the alteration drives tumor development. The findings were published online in Nature.

The results provide a foundation for new research to improve diagnosis and treatment of ependymoma, the third most common brain tumor in children, which remains incurable in 40% of young patients. The findings should also aid efforts to understand and intervene against other cancers, including adult tumors.

The newly discovered alteration involves a gene named RELA. The gene plays a pivotal role in the NF-κB pathway, which regulates inflammation. Researchers have long recognized that this pathway is inappropriately switched on in many adult tumors, and this study marks the first time scientists have found a repeated gene alteration in the central part of the pathway in brain cancer.

Study Details

In this study, 70% of young patients with ependymomas in the front part of the brain carried the RELA alteration and few other genetic changes. The alteration was not found in ependymomas in other regions of the brain.

“In this study, we demonstrate for the first time that a frequent mutation in the heart of the NF-κB pathway is sufficient to transform normal brain cells into cancer cells and drive tumor development,” said co-corresponding author Richard Gilbertson, MD, PhD, Director of the St. Jude Comprehensive Cancer Center. “This should help us to understand how abnormal NF-κB activity drives cancer and to develop new treatments to block that activity.”

The alteration fuses RELA with parts of the C11orf95 gene. This translocation produces abnormal proteins that rapidly cause fatal brain tumors resembling human disease in mouse models.

“This is an exciting finding, not only for understanding the biology of a rare and particularly devastating childhood brain cancer, but also for understanding how it might be effectively treated,” said coauthor Richard K. Wilson, PhD, Director of The Genome Institute at Washington University School of Medicine in St. Louis.

An international study is underway to determine if the C11orf95-RELA translocation might help predict the outcome for ependymoma patients. St. Jude has also developed a test to identify tumors that carry the translocation.


An analytic tool called CICERO developed by St. Jude researchers played a key role in identifying the translocation. Finding the translocation required sifting through 246 billion pieces of genetic information that contain the complete genetic code of the tumor as well as the normal DNA from 41 young patients with ependymoma. The researchers also studied the RNA in 77 ependymomas.

Using CICERO, researchers found abnormalities in RNA that led them to the C11orf95-RELA translocation. The fusion gene was created when a piece of chromosome 11 that houses both the C11orf95 and RELA genes was shattered and incorrectly reassembled.

The result is one of the most commonly occurring translocations ever reported in brain tumors. Of the 41 ependymomas in this study that began in the front part of the brain, 29 tumors had the translocation and made RELA fusion proteins. “The fact the alteration results in abnormal proteins offers a potential new therapeutic target, which is significant for ependymoma,” Dr. Gilbertson said.

Researchers are working to understand how the fusion proteins cause cancer. Evidence suggests that C11orf95 plays a key role by altering the way that RELA moves through the cell and performs its normal functions. Investigators also discovered translocations involving other genes that appear to drive ependymoma.

Dr. Gilbertson, Jinghui Zhang, PhD, and David Ellison, MD, PhD, all of St. Jude Children’s Research Hospital, were the corresponding authors for the Nature study.

The study was funded in part by the Pediatric Cancer Genome Project, grants from the National Institutes of Health, the Collaborative Ependymoma Research Network, and ALSAC.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.