Wir überwinden Grenzen

If a protein becomes too long due to a genetic mutation, this can promote the development of cancer, as researchers at the Medical Center - University of Freiburg and the German Cancer Research Center (DKFZ) have shown for the first time

In certain cases, genetic changes can lead to proteins becoming longer than intended. This can have serious consequences, as researchers from the Medical Center - University of Freiburg and the German Cancer Research Center (DKFZ) have now demonstrated with partners in the German Cancer Consortium (DKTK). They identified and analyzed 3,412 such changes from 62 different tumor types and made the data publicly available to other researchers. Using a tumor-inhibiting protein, they demonstrated the significance of so-called non-stop mutations: If the tumor-inhibiting protein SMAD4 was elongated, it was degraded in the cell significantly faster than normal and was therefore unable to perform its control function adequately. The study was published on July 27, 2020 in the renowned journal Nature Cell Biology.

"We were able to show that a previously ignored class of genetic alterations can play an important role in cancer. This could enable new therapeutic approaches in the future and, above all, help in choosing the best therapy, which increasingly takes into account the genetic profile of a tumor," says Prof. Dr. Sven Diederichs, who heads the Department of Oncology Research in the Department of Thoracic Surgery at the Medical Center - University of Freiburg and the Department of RNA Biology and Cancer at the German Cancer Research Center (DKFZ) in Heidelberg and is a scientist in the German Consortium for Translational Cancer Research (DKTK). "Our results show how important it is to understand supposedly unimportant genetic changes, as they can have a significant influence on the function of cancer genes," says Diederichs.

When the stop switch is missing

The termination of a protein is marked in the genome with a so-called stop codon. It consists of three letters and ensures that the chain of protein building blocks is interrupted. If this stop codon is altered by environmental influences, for example, the protein chain may be continued. "A protein altered in this way can be quickly recognized and disposed of by the cell's purification system. This actually important process can have fatal consequences," explains Diederichs, who, together with his team, examined the SMAD4 protein in pancreatic and intestinal tumors in more detail. SMAD4 normally slows down the development of a benign tumor into a malignant tumor. "Because the excessively long protein is degraded too quickly, it can no longer perform its function and thus promotes cancer," says Diederichs. The study and the newly established database provide an important basis for better investigating this type of mutation, developing new therapeutic approaches based on it and making a more precise decision when choosing a therapy.

Original title of the study: A Pan-Cancer Analysis reveals Nonstop Extension Mutations causing SMAD4 Tumor Suppressor Degradation

DOI: https://doi.org/10.1038/s41556-020-0551-7

Link to the study:
Publication: https://www.nature.com/articles/s41556-020-0551-7
Database: http://nonstopdb.dkfz.de/

Contact:
Prof. Dr. Sven Diederichs
Head of the Department of Oncology Research
Department of Thoracic Surgery
Medical Center - University of Freiburg
and
Head of the Department of RNA Biology and Cancer
German Cancer Research Center (DKFZ) Heidelberg
Phone: 0761 270-77571
sven.diederichs@uniklinik-freiburg.de