Medulloblastoma, a common childhood brain tumor, is classified into 4 subgroups that vary dramatically in terms of the aggressiveness of the disease. For Group 3 and Group 4 tumors, hardly any characteristic genomic changes that drive tumor growth and would make potential targets for drug development have been identified. To propose a solution for this challenge, some investigators were systematically analyzing all genomic alterations in pediatric brain cancer to discover new targets for treatment.
They discovered, from 137 cases of aggressive patients, that in some of tumor genomes large regions of DNA had been deleted or duplicated or had changed their orientation. These varying structural changes had common consequences in all tumors under investigation: One of two oncogenes called GFI1 and GFI1B, which are not active in healthy brain tissue, is transcribed in these tumors and thus contributes to the development of cancer.
They also noticed that different structural changes had moved the oncogene from a usually inactive environment to a position close to DNA sequences called “enhancers”, which are involved in the activation of genes. In mice, the researchers subsequently proved that activated GFI1B leads to the development of brain cancer, providing evidence that the “hijacked” gene enhancers promote the onset of cancer.
This research directly contribute to the development of better treatments for children with brain cancer. Substances that block the effects of the GFI1 and GFI1B oncogenes are already being tested in clinical trials and might now also be used to slow down the growth of aggressive Group 3 and Group 4 medulloblastomas.
Another team, dedicated to investigating the epigenetic regulation of gene activity, compared patterns of DNA methylation across the whole genome from 42 medulloblastomas with the patterns found in healthy control tissue. As discovered in this study, numerous genes in tumor cells exhibited low levels of methylation compared to healthy counterparts. At the same time, they were transcribed significantly more frequently than in healthy cells.
Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 2014; doi:10.1038/nature13379