Understanding Brain Tumors - Mathematical Model of Evolutionary Development

 

Glioblastomas are  among the fastest and aggressively growing brain tumors . The average survival time of glioblastoma patients is only about one year after diagnosis. A crucial characteristic feature of glioblastoma is its irregular infiltration into the adjacent parenchyma. As a result, surgeons rarely succeed in completely removing the tumor. Therefore, glioblastomas frequently relapse despite subsequent radiation- and chemotherapy.

To find out whether there are certain mutations that enable glioblastoma cells to escape from therapy, the scientific team led by Professor Dr. Peter Lichter, Professor Dr. Thomas Höfer and Professor Dr. Guido Reifenberger jointly investigated glioblastoma tissue samples of 50 affected persons in the e:Med alliances SYS-GLIO and SYSMED-NB. By carefully analyzing the tumor inheritance and directly comparing the primary tumor and recurrent tumor tissue of the patients, Dr. Verena Körber, the first author of the published study, was able to formulate a mathematical model of tumor development.

The researchers found that glioblastomas may develop for up to seven years before they are noticed and diagnosed due to associated symptoms and their rapid incease in size. Only three genetic changes drive early development of malignant glioblastomas: an increase in chromosome 7 caused by mutations or a loss of chromosomal material from chromosomes 9p or 10. However, only an additional mutation, which permanently activates telomerase, causes glioblastomas to increase their rapid growth. Telomerase is an enzyme which sustains the telomeres, the endsof the chromosomes. In normal cells, telomeres shorten at each cell division until the telomeric loss results in  a critical telomere length, leading to growth arrest or cell death. This protects the body from diseased cells. By permanently activating telomerase in glioblastomas, cancer cells can infinitely divide and escape cell death.

The inter tumoral characteristics of relapsed tumors after treatment of the primary tumordo not share any characteristic contagious mutations, which is in contrast to early glioblastomas. Relapsed tumors are therefore produced from cancer cells with a variety of mutations.

From this, the researchers conclude that the current standard therapy does not exert any noticeable selection pressure on the cancer cells and that novel forms of treatment are generally needed in order to be able to effectively treat glioblastomas.

 

Original article:

Korber, V., Yang, J., Barah, P., Wu, Y., Stichel, D., Gu, Z., Fletcher, M. N. C., Jones, D., Hentschel, B., Lamszus, K., Tonn, J. C., Schackert, G., Sabel, M., Felsberg, J., Zacher, A., Kaulich, K., Hubschmann, D., Herold-Mende, C., von Deimling, A., Weller, M., Radlwimmer, B., Schlesner, M., Reifenberger, G., Hofer, T. Lichter, P., 2019. Evolutionary Trajectories of IDH(WT) Glioblastomas Reveal a Common Path of Early Tumorigenesis Instigated Years ahead of Initial Diagnosis. Cancer Cell. doi.org/10.1016/j.ccell.2019.02.007
 

Contact person:

Prof. Dr. Peter Lichter, DKFZ Heidelberg, coordinator of  SYS-GLIO

 

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