Scientists from the German Cancer Research Center found in a recent study that only three different genetic alterations drive the early development of malignant glioblastomas. At least one of these three cancer drivers was present in all tumors investigated. However, it is the activation of telomerase that leads to rapid growth. The tumors develop for up to seven years before they become noticeable as symptoms and are diagnosed. However, in contrast to their early development, glioblastomas, which return after therapy, share virtually no concurrent genetic alterations.
Glioblastomas are the most common malignant brain tumors in adults. Since they invade diffusely into healthy brain tissue, surgeons rarely succeed in completely removing the tumor. Therefore, glioblastomas often recur very quickly despite the radiation and chemotherapy following surgery and are then considered incurable according to current knowledge.
"There was a theory that certain mutations might enable glioblastoma cells to survive standard radiochemotherapy and then grow into resistant subclones of the tumor. Our question was: Does the therapy exert a selection pressure on the tumor cells?" said Peter Lichter from the German Cancer Research Center (DKFZ) explaining his current research project. For the development of new drugs that are also effective against relapsed tumors, it is crucial to identify genetic traits that enable cancer cells to evade therapy.
In order to answer this question, Lichter and systems biologist Thomas Hoefer from the DKFZ investigated glioblastoma tissue samples from a total of 50 patients in which they were able to directly compare material from the primary tumor and recurrence. Based on a careful analysis of the tumor genome, the researchers were able to develop a mathematical model of tumor development. They used mutation rates and estimates of tumor cell count. "We simulated the evolutionary pathways of glioblastoma cells and the influence of their gene mutations during tumor growth on the computer," said Hoefer describing the procedure.
The surprising results: At the time of diagnosis, a glioblastoma had already developed over a very long period of time, the researchers calculated up to seven years. "This is hardly conceivable in view of the extremely rapid growth of glioblastomas," said Verena Koerber, the first author of the current publication. "However, we can explain this by the fact that many cancer cells die at the beginning, only at a certain moment does the rapid growth in size start.
The researchers have also discovered this decisive moment: During their early development, all glioblastomas studied showed at least one of three characteristic genetic alterations (gain of chromosome 7, loss of chromosome 9p and 10). These chromosome losses or gains are associated with known, specific "driver mutations" that promote the development of cancer.
However the glioblastomas only start with their rapid growth and increase in size when an additional mutation permanently activates one of the promoters for the telomerase. The enzyme telomerase ensures that the cancer cells can now divide infinitely and do not reach their natural "limit" and die after a certain number of cell divisions. In healthy cells, the telomerase gene is therefore usually not active. During their exponential growth, numerous other mutations accumulate in the cancer cells.
In contrast to the common path of the early developing glioblastomas, the recurrent tumors did not share any characteristically corresponding mutations. They can develop from cancer cells with a variety of different mutation patterns. "This suggests that the current standard therapy does not exert any noticeable selective pressure on the cancer cells and therefore does not promote the development of resistant subclones. This shows that we basically need new forms of treatment in order to effectively treat glioblastomas," said Peter Lichter summarizing the current results.
Verena Koerber, Jing Yang, Pankaj Barah, Yonghe Wu, Damian Stichel, Zuguang Gu, Michael Nai Chung Fletcher, David Jones, Bettina Hentschel, Katrin Lamszus, Jörg Christian Tonn, Gabriele Schackert, Michael Sabel, Jörg Felsberg, Angela Zacher, Kerstin Kaulich, Daniel Hübschmann, Christel Herold-Mende, Andreas von Deimling, Michael Weller, Bernhard Radlwimmer, Matthias Schlesner, Guido Reifenberger, Thomas Hoefer, Peter Lichter:
Evolutionary trajectories of IDH-wildtype glioblastomas reveal a common path of early tumorigenesis instigated years ahead of initial diagnosis.
Cancer Cell 2019, DOI: 10.1016/j.ccell.2019.02.007
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.