Study identifies 2 novel oncogenes that cause childhood brain cancer when activated.
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.
Notes about this genetics and brain cancer research
This work was principally supported by the National Cancer Institute (R01 CA122759), the California Institute for Regenerative Medicine (CIRM LA1-01747), and the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by the German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C, and NGFNplus 01GS0883).
Contact: Susan Gammon, Ph.D. – Sanford-Burnham Medical Research Institute Source:Sanford-Burnham Medical Research Institute press release Image Source: The image is credited to The Armed Forces Institute of Pathology and is in the public domain Original Research:Abstract for “Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma” by Paul A. Northcott, Catherine Lee, Thomas Zichner, Adrian M. Stütz, Serap Erkek, Daisuke Kawauchi, David J. H. Shih, Volker Hovestadt, Marc Zapatka, Dominik Sturm, David T. W. Jones, Marcel Kool, Marc Remke, Florence M. G. Cavalli, Scott Zuyderduyn, Gary D. Bader, Scott VandenBerg, Lourdes Adriana Esparza, Marina Ryzhova, Wei Wang, Andrea Wittmann, Sebastian Stark, Laura Sieber, Huriye Seker-Cin, Linda Linke, Fabian Kratochwil, Natalie Jäger, Ivo Buchhalter, Charles D. Imbusch, Gideon Zipprich, Benjamin Raeder, Sabine Schmidt Nicolle Diessl, Stephan Wolf, Stefan Wiemann, Benedikt Brors, Chris Lawerenz, Jürgen Eils, Hans-Jörg Warnatz, Thomas Risch, Marie-Laure Yaspo, Ursula D. Weber, Cynthia C. Bartholomae, Christof von Kalle, Eszter Turányi, Peter Hauser, Emma Sanden, Anna Darabi, Peter Siesjö, Jaroslav Sterba, Karel Zitterbart, David Sumerauer, Peter van Sluis, Rogier Versteeg, Richard Volckmann, Jan Koster, Martin U. Schuhmann, Martin Ebinger, H. Leighton Grimes, Giles W. Robinson, Amar Gajjar, Martin Mynarek, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Andreas E. Kulozik, Andreas von Deimling, Olaf Witt, Roland Eils, Richard J. Gilbertson, Andrey Korshunov, Michael D. Taylor, Peter Lichter, Jan O. Korbel, Robert J. Wechsler-Reya and Stefan M. Pfister in Nature. Published online June 22 2014 doi:10.1038/nature13379