A new collaborative study carried out by researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham), UC San Diego, the German Cancer Research Center, the University of Heidelberg (Germany), and 33 other research institutions has identified two oncogenes, called GFI1 and GFI1B, that drive the development of medulloblastoma, the most common malignant brain tumor in children.
The findings, published June 22 in Nature, suggest that GFI1 and GFI1B are worthy gene candidates for molecular-targeted therapy.
"Using state-of-the-art technologies to survey the genomes of tumors derived from medulloblastoma patients, we have identified new oncogenes that drive the growth of a considerable proportion of Group 3 and 4 medulloblastomas. Patients with Group 3 and 4 tumors have the poorest outcomes and the fewest therapeutic options of all medulloblastoma patients," said Robert Wechsler-Reya, Ph.D., director of the Tumor Initiation and Maintenance Program at Sanford-Burnham, and co-senior author of the paper.
Current therapy for patients with medulloblastoma includes surgery, radiation, and high-dose chemotherapy. Although these therapies have a significant impact on tumor growth, many children ultimately relapse and die of the disease. Moreover, survivors suffer profound long-term side effects -- including cognitive deficits and increased susceptibility to other cancers -- as a result of the aggressive treatment.
"Going forward, we expect that the genetic profiles of medulloblastoma tumors will lead to markers that allow us to adjust a patient's therapy to target the genes that are actually driving the growth of the tumor. Our findings are promising in that they may ultimately lead to genetically informed clinical trials of new agents that target the genetic variations we discovered," said Wechsler-Reya.
Hijacking gene enhancers
The study also revealed how the oncogenes -- inactive in normal healthy brains -- become activated in medulloblastoma by "hijacking" unrelated DNA elements called "enhancers." Enhancers are short regions of DNA that activate genes, and there are hundreds of thousands of them in the human genome.
"Chromosome rearrangements that merge oncogenes with enhancers have been observed in lymphoid cancers, such as non-Hodgkin's lymphoma," said Wechsler-Reya. "But this is the first report of this phenomenon in brain tumors."
Chromosome rearrangements occur when segments of the DNA double helix are deleted, amplified, or swap positions -- disrupting the normal order and sequence of genes.
"Gene rearrangements that activate oncogenes have broad-reaching implications for cancer genomics," said Paul Northcott, Ph.D., senior researcher at the German Cancer Research Center and co-first author of the study. "It will be interesting to re-examine the genomes of other cancers using today's sophisticated analytical tools to see if the enhancer hijacking process of activating oncogenes is broader than we currently understand.
"Moreover, these rearrangements leading to GFI1 and GFI1B activation open up promising new avenues for the treatment of medulloblastoma patients, as novel therapies specifically targeting enhancers are currently making their way into clinical trials for other cancers. Targeting enhancers bypasses some of the caveats associated with the direct targeting of oncogenes themselves, which can be notoriously difficult to inhibit," added Northcott.
- Robert J. Wechsler-Reya, Stefan M. Pfister et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature, 2014; DOI: 10.1038/nature13379
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