Why the same DNA damage causes cancer in some people but not others

The discovery 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 consider inherited genetics and the diversity found across human populations.

Published in Nature, the mouse study also indicates that a patient's genetic background could affect how they respond to cancer treatments that damage DNA. This strengthens the argument for diagnostic and treatment strategies tailored more closely to each individual.

Why DNA Damage Does Not Affect Everyone Equally

Cancer begins when DNA errors, known as mutations, accumulate inside cells. These changes can cause cells to multiply 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. Inherited genetic differences can also influence how many mutations build up and how cells respond to them.

Yet people exposed to the same risks do not always experience the same outcome. Most smokers never develop lung cancer, while some people who have never smoked do. Scientists have long suspected that inherited genetics helps explain these differences, but obtaining direct evidence from human studies has been difficult.

People within and across populations differ in their lifestyles, environments, and exposure histories. These variations make it challenging to isolate the influence of genetic background from all the other factors that can affect cancer risk.

The research grew out of years of international collaboration involving the University of Cambridge, the University of Edinburgh, and institutions across Europe and the US. The work was co-led by Professor Duncan Odom, Dr. Sarah Aitken and Professor Martin Taylor.

Testing Cancer Risk Under Controlled Conditions

Much of the experimental work took place at the Cancer Research UK (CRUK) Cambridge Institute at the University of Cambridge. The researchers designed a method that allowed them to keep environmental conditions consistent and directly test whether genetic background changes how tumors begin and evolve.

They bred four strains of mice with different levels of susceptibility to liver cancer. Together, the strains represented a degree of genetic diversity comparable to that found among human populations.

Each mouse received one dose of the liver carcinogen diethylnitrosamine (DEN). DEN is present in tobacco smoke and some processed foods. It damages DNA in liver cells and can create mutations that start tumor growth.

Every mouse received the same dose at the same age, 15 days old, under carefully controlled conditions. This allowed the team to remove much of the environmental variation that complicates cancer studies involving humans.

The scientists then sequenced the genomes of nearly 600 tumors. They examined changes in gene activity and studied untreated mice to compare the rates of spontaneous tumor formation among the four strains.

Using these results, the team reconstructed the development of each tumor, beginning with the original mutation that triggered the cancer.

Inherited Genes Steered Tumor Evolution

Tumors in all four mouse strains almost always developed a driver mutation that activated the same cancer-promoting signaling system, known as the MAPK pathway.

The MAPK pathway is a sequence of molecular signals that regulates essential processes such as cell growth and cell differentiation. It is involved in many forms of cancer.

Although the tumors frequently activated the same broad pathway, they did not all evolve in the same way. The specific driver mutations that appeared depended on the inherited genetics of each mouse.

Those mutations also changed the activity of other signaling pathways associated with cancer. In addition, certain genetic backgrounds showed a striking tendency toward whole-genome duplication, an event in which the complete set of chromosomes is copied.

Senior author Professor Duncan Odom, who led the research while at the CRUK Cambridge Institute and is now based at DKFZ (German Cancer Research Centre) in Heidelberg, Germany, said: "Cancer does not arise entirely by chance. Although tumors often reach the same biological endpoint, the path to that endpoint is determined by an individual's genetic background.

"We've been able to show for the first time the extent to which genetic background influences both the mutation processes and the pathways leading to tumor development."

Implications for Cancer Screening and Treatment

The researchers say the findings could have important consequences for precision medicine and cancer screening.

First author Dr. Sarah Aitken, Assistant Professor at Yale School of Medicine, who also worked on the research at the CRUK Cambridge Institute, said: "If genetic background influences both cancer risk and the evolutionary trajectory of tumors, future cancer prevention and screening strategies will need to take into account inherited genetics and population diversity.

"Similarly, how people respond to cancer drugs is likely to differ depending on their inherited genetics, and so we may need to tailor our diagnostics and treatments accordingly."

Cancer Research UK research information lead Dr. Sam Godfrey said: "This study gives us a fascinating hint that our inherited genes might have a big influence on the way that cancers develop after DNA damage.

"We still need to see more research before we can understand what this means in humans, but this finding could change our understanding of how cancer starts, and lead to more powerful and precise ways of tackling cancer."

Because the experiments were conducted in mice, additional research will be necessary to determine how closely the findings apply to humans. Still, the results provide evidence that cancer development is shaped not only by environmental damage and acquired mutations, but also by the genetic background in which those mutations occur.

The research was largely funded by Cancer Research UK, the Medical Research Council, European Research Council and Wellcome.