Surprising genetic variety in childhood brain cancer
Medulloblastoma is a malignant tumor of the cerebellum. Medulloblastoma can occur at any age, but it most commonly affects children. Medulloblastomas are classified in four distinct molecular-biological subgroups that are characterized by widely varying disease courses and chances of cure. Tumors of groups 3 and 4 are particularly common in children. However, little is understood up to know about these two types. Therefore, treatment of cancers of this group is often very difficult. "Even if patients respond well to the treatment, their cancer is often being cured at high costs, because the therapy can have negative effects on the brain, the IQ and the children's further development," said Stefan Pfister from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), who is also the director of the Hopp Children's Tumor Center at the NCT* Heidelberg (KiTZ) and pediatric oncologist at the Heidelberg University Hospital.
An international research team under the leadership of scientists from the German Cancer Research Center has now analyzed almost 500 medulloblastomas. They discovered that these brain cancers exhibit a much wider genetic variety than previously thought. In groups 3 and 4, in particular, more than half of the underlying genetic alterations had been completely unknown until now. "While we could previously explain only 30 percent of tumors in these groups on a molecular-biological basis, we have now reached 80 percent," emphasized Peter Lichter from the DKFZ.
This finding helps classify subgroups of medulloblastoma more precisely and treat them more individually in order to improve curative chances and reduce the risk for severe side effects. Lichter said that in some cases this could already be done using available agents. "In other subtypes we now understand the genetic causes for the first time so that we can search very specifically for new therapy approaches," said Lichter.
In addition, the scientists have identified alterations at the level of gene regulation as a typical mechanism for the occurrence of medulloblastoma. In a process called "enhancer hijacking", cancer genes frequently capture DNA sequences called "enhancers". Structural changes in the DNA cause an oncogene that should normally be inactive to move to a different position where it is activated by an enhancer, thus promoting the onset of cancer.
This work was supported by the International Cancer Genome Cornsortium PedBrain Tumour Project, funded by the German Cancer Aid and by the German Federal Ministry of Education and Research.
Paul A. Northcott, Ivo Buchhalter, A. Sorana Morrissy, Volker Hovestadt, Joachim Weischenfeldt, Tobias Ehrenberger, Susanne Groebner, Maia Segura-Wang, Thomas Zichner, Vasilisa Rudneva, Hans-Jörg Warnatz, Nikos Sidiropoulos, Aaron H. Phillips, Steven Schumacher, Kortine Kleinheinz, Sebastian M. Waszak, Serap Erkek, David T.W. Jones, Barbara C. Worst, Marcel Kool, Marc Zapatka, Natalie Jäger, Lukas Chavez, Barbara Hutter, Matthias Bieg, Nagarajan Paramasivam, Michael Heinold, Zuguang Gu, Naveed Ishaque, Christina Jäger-Schmidt, Charles D. Imbusch, Alke Jugold, Daniel Hu?bschmann, Thomas Risch, Vyacheslav Amstislavskiy, Francisco German Rodriguez Gonzalez, Ursula D. Weber, Stephan Wolf, Giles W. Robinson, Xin Zhou, Gang Wu, David Finkelstein, Yanling Liu, Florence M.G. Cavalli, Betty Luu, Vijay Ramaswamy, Xiaochong Wu, Jan Koster, Marina Ryzhova, Yoon-Jae Cho, Scott L. Pomeroy, Christel Herold-Mende, Martin Schuhmann, Martin Ebinger, Linda M. Liau, Jaume Mora, Roger E. McLendon, Nada Jabado, Toshihiro Kumabe, Eric Chuah, Yussanne Ma, Richard A. Moore, Andrew J. Mungall, Karen L. Mungall, Nina Thiessen, Kane Tse, Tina Wong, Steven J.M. Jones, Olaf Witt, Till Milde, Andreas von Deimling, David Capper, Andrey Korshunov, Marie-Laure Yaspo, Richard Kriwacki, Amar Gajjar, Jinghui Zhang, Rameen Beroukhim, Ernest Fraenkel, Jan O. Korbel, Benedikt Brors, Matthias Schlesner, Roland Eils, Marco A. Marra, Stefan M. Pfister, Michael D. Taylor and Peter Lichter: Multidimensional molecular portraits of medulloblastoma subtypes. Nature 2017, DOI: 10.1038/nature22973
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.
The Hopp Children's Tumor Center at the NCT Heidelberg (KiTZ) is a joint institution of the Heidelberg University Hospital and the German Cancer Research Center (DKFZ). As a therapy and research center for oncology and hematology in children and adolescents, KiTZ is committed to closely linking promising research approaches with patient care- from diagnosis to treatment and aftercare. Children suffering from cancer, especially those with no established therapy options left, are given an individual therapy plan in the KiTZ, which is created by interdisciplinary expert groups in so-called tumor boards. The participation of young patients in clinical trials ensures access to new therapy options. Thus, the KiTZ is a pioneering platform for transferring research knowledge from the laboratory to the clinic.
Dr. Sibylle Kohlstädt