Strategic Communication and Public Relations

Traces of immortality in tumor DNA

No. 06 | 05/02/2020 | by Koh

To gain an infinite lifespan, cancer cells need to maintain the ends of their chromosomes, known as telomeres. They achieve this in various different ways. Scientists from the German Cancer Research Center systematically investigated more than 2,500 tumor genomes of 36 types of cancer to find out how these mechanisms are manifest in changes in the DNA. Active lengthening of the telomeres is one of the hallmarks of all cancer cells and hence an important focus in developing targeted treatments. The study is part of the Pan-Cancer Analysis of Whole Genomes (PCAWG).

Intact telomeres, the end structures of the chromosomes, are a prerequisite for the immortality of tumor cells.
© AJC1, Wikimedia Commons

Healthy body cells have a natural expiry date defined by the length of their telomeres. Telomeres are part of DNA and protect the end of the chromosomes. They become shorter each time the cell divides, however, until a minimum length is reached – the telomere has then been used up so to speak. Stem cells are the only type of cells to produce the 'immortality enzyme' telomerase, which can lengthen the telomeres again. All other cells stop dividing after around 50 cycles.

Cancer cells depend on intact telomeres for unlimited cell division. Earlier studies showed that around 85 percent of all tumors upregulate telomerase via different mechanisms. The remaining tumors use alternative mechanisms to lengthen telomeres.
A team of researchers led by Lars Feuerbach from the German Cancer Research Center (DKFZ) studied more than 2,500 tumor samples to gain a better understanding of these mechanisms, in particular those that have not been well researched to date. The study is part of the Pan-Cancer Analysis of Whole Genomes (PCAWG).

The PCAWG researchers found DNA mutations that point to one of the two known mechanisms of telomere lengthening in only 13 percent of the cases studied. As lead author Lina Sieverling explained, "In the vast majority of the 2,500 cancer cases studied, we observed increased activity of the telomerase gene but without any changes in the genome that could explain this. Epigenetic factors that do not leave any trace in the genome might be partly responsible here."

Of the 13 percent of those tumors whose DNA showed indications of telomere lengthening, only 64 cases pointed to the alternative mechanisms.

The researchers discovered two peculiarities in these tumors: Telomeres usually consist of hundreds of repetitions of the same sequence of six DNA bases. In the telomeres with alternative lengthening mechanisms, however, variations of the normal telomere sequences are often found. Moreover, small fragments of the telomeres are very often integrated into other parts of the genome in these tumor cells.

In certain types of cancer, particularly in children, one of the factors that determine the aggressiveness of the tumor is known to be the mechanism by which the telomeres of the cancer cells are lengthened. This is the case in medulloblastomas, for example, which carry a worse prognosis if the cancer cells use the alternative mechanism.

"At the moment, we cannot tell whether and, if so, in what way these two findings are important or whether they affect the course of disease in cancer patients," principal investigator Lars Feuerbach explained. "Active lengthening of the telomeres is one of the weak points in all cancer cells and hence an important focus in developing targeted treatments," he added. "To do so, a precise knowledge of all the underlying molecular processes is vital."

Genomic footprints of activated telomere maintenance mechanisms in cancer: Lina Sieverling, Chen Hong, Sandra D. Koser, Philip Ginsbach, Kortine Kleinheinz, Barbara Hutter, Delia M. Braun, Isidro Cortés-Ciriano, Ruibin Xi, Rolf Kabbe, Peter J. Park, Roland Eils, Matthias Schlesner, PCAWG-Structural Variation Working Group, Benedikt Brors, Karsten Rippe, David T.W. Jones, Lars Feuerbach & PCAWG Consortium
Nature Communications 2020. DOI: 10.1038/s41467-019-13824-9

 

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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