Oncology researchers have discovered that an abnormal fused gene that drives pediatric brain tumors poses a triple threat, operating simultaneously through three distinct biologic mechanisms—the first such example in cancer biology. The study was published by Bandopadhayay et al in Nature Genetics.
This finding potentially offers triple benefits as well: more accurate diagnoses, clues for more effective treatments, and new insights into molecular processes underlying other types of cancer.
“The gene rearrangement we investigated offers a great candidate for a precision medicine approach in improving treatment for children with this type of brain tumor,” said study co-leader Adam C. Resnick, PhD, a neuro-oncology researcher in the Division of Neurosurgery at The Children's Hospital of Philadelphia. “Our research exemplifies the transformative power of large multi-institutional research collaborations in sharing and empowering data from new diagnostic technologies.”
Dr. Resnick's co–study leaders were Keith L. Ligon, MD, PhD, and Rameen Beroukhim, MD, PhD, both of Dana-Farber Cancer Institute, with coauthors from nearly 20 centers in five countries.
The scientists investigated pediatric low-grade gliomas, a varied group collectively representing the most common pediatric brain tumor. Drawing on samples gathered by the Children's Brain Tumor Tissue Consortium and a consortium at Dana-Farber, as well as additional, previously uncurated datasets, they analyzed the genomes of 249 such tumors—the largest amount of data available for pediatric low-grade gliomas.
Among the 249 samples were 19 tumors classified as angiocentric gliomas, which occur in the brain's temporal lobe. In virtually all the angiocentric gliomas, the researchers found that two genes, MYB and QKI, had fused together to express an abnormal, cancer-driving fusion protein.
The MYB-QKI fusion gene promotes tumor formation through three simultaneous mechanisms. Unlike normal proteins expressed by the MYB genes, the rearranged gene expresses truncated, constitutively active proteins that give rise to cancer. Secondly, enhancer regions in or near QKI's DNA move in proximity to MYB during the fusion event. This causes abnormal expression of the fusion protein in brain tissues, leading to a feedback loop that drives cell proliferation. Finally, the fusion gene disrupts QKI's protective role as a tumor suppressor.
These disease-causing events provide new examples of how genomic dysregulation interacts and synergizes with epigenomic dysregulation. Epigenomic dysregulation comprises complex changes in gene expression not caused by changes in the DNA sequence of protein-coding elements.
The current research has important implications for clinicians. Identifying the MYB-QKI fusion gene as a defining event in angiocentric glioma may allow oncologists to better diagnose this subtype of tumor, guiding them toward directed therapies less likely to overtreat or undertreat children. Furthermore, although there do not appear to be existing drugs to target the abnormal MYB protein, there are potential drugs that may be effective against the type of epigenomic dysregulation seen in these tumors.
In addition, Dr. Resnick said, "Now that we better understand the three mechanisms involved, we may be better able to craft our treatment strategies against any of those mechanisms."
Finally, he concluded, “the study expands our current understanding of cancer, by focusing attention on the multiple mechanisms occurring simultaneously, and bringing into relief how gene fusions may give rise to epigenomic dysregulation. Gene fusions occur in many other cancers in both children and adults, so our findings may apply more broadly to other cancers."