Brain tumors are the primary cause of cancer mortality in children. Even if a cure is possible, young patients often suffer from the stressful treatment which can be harmful to the developing brain. The most common childhood brain tumors are medulloblastoma and pylocytic astrocytoma.
In order to find new target structures for more gentle treatment methods, cancer researchers are systematically analyzing all changes in the genetic material of such tumors. This is the mission of the PedBrain consortium, which was launched in 2010 as the first German part in the International Cancer Genome Consortium (ICGC). The PedBrain Tumor network, which is coordinated by Professor Peter Lichter of DKFZ and Professor Roland Eils (DKFZ and Heidelberg University), has now published, jointly with numerous collaboration partners, an evaluation of the first 125 genome analyses of medulloblastomas.
"We can already see great differences in the genomes of medulloblastomas from one patient to the next," says Peter Lichter. "But we have also identified a number of frequent and characteristic genomic alterations that may lead the way to developing new methods of diagnosis and treatment."
Brain tumors with four sets of chromosomes are particularly aggressive
A high percentage of medulloblastomas -- particularly among those with very malignant progression -- has four sets of chromosomes instead of two as normal. Medulloblastomas are classified into four groups according to aggressiveness. In the study, about half of tumors belonging to groups 3 and 4, which are very difficult to treat, were found to have this aberration. "It is not proven that the extra chromosomes cause cancer. But it is certain that they occur at a very early stage of the cancerous process," Lichter explains.
Cells with four sets of chromosomes have been found in several types of cancer. However, this genomic aberration also offers a chance of specifically attacking tumors. At the German Cancer Research Center (DKFZ), researchers collaborating with Bayer Healthcare are currently working to develop an agent which specifically inhibits the growth of cells with more than two sets of chromosomes.
About one third of individual mutations in medulloblastoma are found in genes that play a part in what are called epigenetic modifications. "This finding shows once more that drugs influencing such modifications will become increasingly important in cancer treatment," says Professor Dr. Stefan Pfister, a pediatrician and molecular biologist. DKFZ and Heidelberg University Hospital are already testing such promising substances to treat specific pediatric tumors.
The total number of genomic alterations in medulloblastoma increases with the age of patients. "Although many scientists have supposed that there is such a correlation, it has never been documented before," Stefan Pfister explains. "We suspect, however, that the foundation for medulloblastoma is laid already during embryonic development."
For the first time, the PedBrain researchers have also found what are called fusion genes in medulloblastoma. Such genes are formed when, due to genetic accidents, cancer-promoting genes are fused together and new proteins occur as a result. Such fusion genes cause a number of cancers such as chronic myelogenous leukemia (CML). For this cancer, researchers have succeeded in developing a very effective drug against the BCR-ABL fusion gene, which is highly specific for leukemia cells.
"Along with a multitude of individually occurring mutations, we were able to define a number of typical groups of mutations, which will show us the way to new strategies of fighting medulloblastoma," says Peter Lichter to sum up. "Given the genetic complexity and heterogeneity of this tumor type, a useful future approach would be to analyze the tumor genome in each affected child in order to identify the most promising treatment."
International collaboration to analyze tumor genomes
The International Cancer Genome Consortium (ICGC), a network of scientists from currently 14 countries, aims to obtain a comprehensive description of genomic and epigenomic changes in all relevant cancers. Germany participates with the PedBrain Tumor project to analyze pediatric brain tumors (medulloblastoma, which in Germany affects approximately 100 children each year; and pilocytic astrocytoma, which is diagnosed in about 200 children each year). As part of the PedBrain Tumor project, 300 tumor samples of each tumor type will be analyzed, along with the same number of healthy samples from the same patients in order to identify changes that are cancer-specific.
The PedBrain Tumor network consists of researchers from seven institutes led by project coordinator Peter Lichter of DKFZ. Alongside DKFZ, participating project partners in Heidelberg are: the National Center for Tumor Diseases (NCT), Heidelberg University and the University Hospital, and the European Molecular Biology Laboratory (EMBL). In addition, scientists from Düsseldorf University Hospital and the Max Planck Institute for Molecular Genetics in Berlin have taken on tasks within the network project.
PedBrain Tumor was supported by the German Cancer Aid (Deutsche Krebshilfe) with funds of eight million euros and has been funded by the Federal Ministy of Education and Research (BMBF) since 1 July 2012 with another seven million euros.
Furthermore, the PedBrain researchers from DKFZ have contributed results of their medulloblastoma analyses to another two publications in the current issue of Nature. Besides the PedBrain Tumor network, scientists from DKFZ are collaborating in the genome analysis of early prostate cancer (coordination: DKFZ and University Medical Center Hamburg-Eppendorf) and B cell lymphomas (coordination: University of Kiel).
- David T. W. Jones, Natalie Jäger, Marcel Kool, Thomas Zichner, Barbara Hutter, Marc Sultan, Yoon-Jae Cho, Trevor J. Pugh, Volker Hovestadt, Adrian M. Stütz, Tobias Rausch, Hans-Jörg Warnatz, Marina Ryzhova, Sebastian Bender, Dominik Sturm, Sabrina Pleier, Huriye Cin, Elke Pfaff, Laura Sieber, Andrea Wittmann, Marc Remke, Hendrik Witt, Sonja Hutter, Theophilos Tzaridis, Joachim Weischenfeldt, Benjamin Raeder, Meryem Avci, Vyacheslav Amstislavskiy, Marc Zapatka, Ursula D. Weber, Qi Wang, Bärbel Lasitschka, Cynthia C. Bartholomae, Manfred Schmidt, Christof von Kalle, Volker Ast, Chris Lawerenz, Jürgen Eils, Rolf Kabbe, Vladimir Benes, Peter van Sluis, Jan Koster, Richard Volckmann, David Shih, Matthew J. Betts, Robert B. Russell, Simona Coco, Gian Paolo Tonini, Ulrich Schüller, Volkmar Hans, Norbert Graf, Yoo-Jin Kim, Camelia Monoranu, Wolfgang Roggendorf, Andreas Unterberg, Christel Herold-Mende, Till Milde, Andreas E. Kulozik, Andreas von Deimling, Olaf Witt, Eberhard Maass, Jochen Rössler, Martin Ebinger, Martin U. Schuhmann, Michael C. Frühwald, Martin Hasselblatt, Nada Jabado, Stefan Rutkowski, André O. von Bueren, Dan Williamson, Steven C. Clifford, Martin G. McCabe, V. Peter Collins, Stephan Wolf, Stefan Wiemann, Hans Lehrach, Benedikt Brors, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Paul A. Northcott, Michael D. Taylor, Matthew Meyerson, Scott L. Pomeroy, Marie-Laure Yaspo, Jan O. Korbel, Andrey Korshunov, Roland Eils, Stefan M. Pfister, Peter Lichter. Dissecting the genomic complexity underlying medulloblastoma. Nature, 2012; DOI: 10.1038/nature11284
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