Scientists have discovered the first direct evidence that genetic genetics strongly influence cancer risk and may help determine how tumors develop over time. The results show that the genes a person is born with can interact with mutations acquired later in life to shape the evolutionary path that tumors follow.
This finding may help explain why people living in similar environments can face very different cancer risks. It also suggests that future approaches to cancer prevention and screening may need to take into account genetics and the diversity found across human populations.
Published in naturemouse studies have also shown that a patient’s genetic background can influence how they respond to cancer treatments that damage their DNA. This strengthens the argument for diagnostic and treatment strategies more closely tailored to each individual.
Why DNA damage doesn’t affect everyone equally
Cancer begins when DNA errors, known as mutations, accumulate in cells. These changes can cause cells to grow too quickly and ignore signals that normally tell damaged cells to die before they become dangerous.
Environmental factors such as cigarette smoke and sunlight can increase DNA damage. Genetic genetic differences can also affect how many mutations accumulate and how cells respond to them.
However, people exposed to the same risks do not always experience the same outcomes. Most smokers do not develop lung cancer, but some people who have never smoked do develop lung cancer. Scientists have long suspected that genetics could help explain these differences, but direct evidence from human studies has been difficult to obtain.
People differ in their lifestyles, environments, and exposure histories within and between populations. These variations make it difficult to separate the effects of genetic background from all other factors that may influence cancer risk.
The research resulted from many years of international collaboration involving the University of Cambridge, the University of Edinburgh, and institutions in Europe and the United States. The research was co-led by Professor Duncan Odom, Dr Sarah Aitken and Professor Martin Taylor.
Testing for cancer risk under controlled conditions
Much of the experimental work was carried out at the Cancer Research UK (CRUK) Cambridge Laboratory at the University of Cambridge. The researchers designed a method that allows them to keep environmental conditions consistent and directly test whether genetic background changes the way tumors develop and evolve.
They bred four strains of mice with different levels of susceptibility to liver cancer. Together, these strains exhibited a degree of genetic diversity comparable to that seen among human populations.
Each mouse received a single dose of diethylnitrosamine (DEN), a liver carcinogen. DEN is present in tobacco smoke and some processed foods. It can damage the DNA of liver cells and cause mutations that start tumor growth.
All mice were given the same dose at the same age, 15 days after birth, under carefully controlled conditions. This allowed the research team to eliminate much of the environmental variation that complicates cancer research in humans.
Scientists then sequenced the genomes of nearly 600 tumors. They looked at changes in gene activity, studied untreated mice, and compared spontaneous tumor formation rates among the four strains.
Using these results, the team reconstructed the development of each tumor, starting with the original mutation that triggered the cancer.
Inherited genes guide tumor evolution
Tumors in all four mouse strains almost always developed driver mutations that activated the same cancer-promoting signaling system known as the MAPK pathway.
The MAPK pathway is a set of molecular signals that control important processes such as cell proliferation and differentiation. It is involved in many forms of cancer.
Although tumors frequently activated the same broad pathways, they did not all evolve in the same way. The specific driver mutations that emerged depended on each mouse’s genetics.
These mutations also altered the activity of other signaling pathways associated with cancer. Furthermore, certain genetic backgrounds showed a pronounced tendency toward whole-genome duplication, a phenomenon in which a complete set of chromosomes is copied.
Lead author Professor Duncan Odom, who led the study while at the CRUK Cambridge Institute and is now based at DKFZ (German Cancer Research Center) in Heidelberg, Germany, said: “Cancer does not arise completely by chance. Tumors often reach the same biological endpoint, but the path to that endpoint is determined by the individual’s genetic background.”
“We were able to show for the first time the extent to which genetic background influences both the mutational process and the pathway leading to tumor development.”
Implications for cancer screening and treatment
Researchers say this finding could have important implications for precision medicine and cancer screening.
“If genetic background influences both cancer risk and tumor evolutionary trajectories, future cancer prevention and screening strategies will need to take genetics and population diversity into account,” said lead author Dr. Sarah Aitken, assistant professor at Yale School of Medicine, who also worked on the study at the CRUK Cambridge Institute.
“Similarly, people’s responses to cancer drugs are likely to vary depending on the genes they have inherited, and diagnosis and treatment may need to be adjusted accordingly.”
Dr Sam Godfrey, head of research information at Cancer Research UK, said: “This study provides an exciting hint that the genes we inherit may have a major influence on how cancer develops following DNA damage.”
“More research is still needed to understand what this means in humans, but this discovery could change our understanding of how cancer develops and lead to more powerful and precise ways to fight cancer.”
Because the experiment was conducted on mice, additional research will be needed to determine how well the findings apply to humans. Still, the results provide evidence that cancer development is shaped not only by environmental insults and acquired mutations, but also by the genetic context in which those mutations occur.
This research was primarily funded by Cancer Research UK, Medical Research Council, European Research Council and Wellcome.
