Individual cancer risk: how genes protect

“Good genes” against cancer Individual cancer risk: how genes protect

05.11.2020 | Author / Publisher: Dr. Martin Ballaschk * / Dr. Ilka Ottleben

Some people live very healthily and continue to get cancer. Others don’t care about a healthy lifestyle at all and stay healthy. Coincidence? Or is it in our genes whether we will develop a malignant tumor in our lifetime or not? To some extent, as a Berlin research group has now been able to prove in a mouse model. One key is individual differences in the effects of cancerous mutations.

Berlin – It sounds paradoxical: there are people who smoke a chain and stay healthy for life, and others pay close attention to their health and develop cancer. Is it just a coincidence if someone has a malignant tumor or not? Not really, because anyone who has inherited “good genes” could stay healthy even if they carry cancerous mutations.

The risk of cancer depends on many genes

The origin of each tumor is a mutation, triggered by poisons, viruses, radiation or simply accidental copy errors when the genetic material is duplicated before each cell division. If such DNA changes occur in cancer genes, that is, genes that regulate cell growth or division, for example, those processes can get out of control and cancer growths develop.

The extent to which a mutation in a cancerous gene “affects” and actually causes tumors, however, largely depends on the combination of the many genetic variants in an organism. A Berlin research team from the Max Planck Institute for Molecular Genetics and the Charité – Universitätsmedizin Berlin has examined this “genetic background” and its function using the example of colon cancer in mice and has now presented it in the specialized journal Cancer Research. According to this, genes distributed throughout the genome influence the cell’s ability to cushion the damaging effects of a tumor mutation.

By comparing two different strains of laboratory mice, examining individual chromosomes and gene activity in diseased tissues, the research team identified numerous gene variants that influence cancer risk in mice. These include genes that control cell division and growth in humans and play an important role in embryonic development and tissue homeostasis in the gut. Spread across a single chromosome, the team was able to identify 58 genes that are read at different levels in the two mouse strains.

The study was conducted under the direction of Bernhard G. Herrmann, director of the Max Planck Institute for Molecular Genetics (MPIMG) and the Institute of Medical Genetics at the Charité – Universitätsmedizin Berlin, and Markus Morkel, scientist at the Institute of Pathology at the Charité and former employee of the Herrmann working group.

Reproductive strains of laboratory mice are otherwise susceptible to cancer

“The genome of every human being is made up of a unique combination of many thousands of gene variants that determine our individual characteristics and abilities,” says Herrmann. “We therefore suspected that gene variants also affect different susceptibility to disease, such as the development of tumors in response to a mutation that causes the tumor.”

For their study, Herrmann and Morkel’s team compared lab mice from the cancer-prone “Black-6” inbred strain with those from the “PWD” breeding line. “The animals come from different subspecies of the house mouse and therefore show thousands of genetic differences,” says Alexandra Farrall, one of the two first authors of the work.

The researchers studied how the animals reacted to a change in the APC tumor suppressor gene, which is responsible for 80 percent of colon cancer cases in humans. In mice and humans, this mutation leads to the formation of adenomas (“polyps”), growths of the intestinal mucosa that can degenerate over time. More than 100 adenomas formed in the intestines of the Black-6 mice with the mutation at three months of age.

When the researchers crossed the Black 6 mice with PWD strain animals, the offspring developed fewer than ten polyps, despite the damaging APC mutation. “The genome of the PWD mice was responsible for ensuring that the mutation in the APC gene caused almost no cancer,” says Farrall.

Many genes work together against the formation of tumors

But what factors ensure that mice are protected from adenoma formation? To find out, the research team replaced the single chromosomes of the Black 6 mice with chromosomes from the PWD mouse. “In fact, nearly all of the PWD chromosomes tested significantly reduced the risk of cancer in mice, although not as much as the entire genome,” says Matthias Lienhard, who is also the first author.

The researchers then focused on chromosome 5. “The sections of the chromosome that statistically significantly reduce cancer risk extend to the entire chromosome,” Lienhard explains.

The expression level of most of these genes on chromosome 5 also remained stable in the adenoma tissue. This allows them to counter the tumor-driving mechanisms triggered by the loss of APC. Nor do they differ significantly between parents and their offspring, so their anti-cancer effects appear to be hereditary.

“The gene variants of the PWD strain had a particular effect on stem cells in the gut by weakening the growth-stimulating effect of the APC mutation,” says Morkel. “They also presumably lead to the degenerated stem cells being rejected from the tissue at an early stage, so that an adenoma cannot develop in the first place.”

Also relevant for human cancers

By comparing the genetic variants of mouse chromosome 5 with the genomes of people with colon cancer, the researchers found eight gene variants that are severely underrepresented in this group of people. This suggests that these genetic variants could have a preventive effect on colon cancer in humans.

“In our study, we provide evidence that an individual’s genetic makeup can also control the genetic changes that cause severe cancer and that individual cancer risk has a decisive influence,” Herrmann says.

“Individually, the different genetic variants are likely to have only minor effects and therefore probably have not been discovered in association studies in humans,” says Morkel. “In combination, however, they can work together and create solid cancer protection.”

Scientists argue that analyzing the cancer protection mechanisms of the genome should play a more important role in cancer research in the future. They hope their findings will enable new strategies to improve personalized cancer screening and cancer treatments.

Originalpublikation: Farrall AL, Lienhard M, et al. (2020): Genetic variants encoded PWD / Ph modulate Wnt / β-catenin cellular response to suppress the formation of ApcMin-activated intestinal tumors. Cancer Research, OnlineFirst version was published November 5, 2020, doi: 10.1158 / 0008-5472.CAN-20-1480

* Dr. M. Ballaschk: Max Planck Institute for Molecular Genetics, 14195 Berlin

(ID: 46973805)