Why identical cancer risks can lead to different outcomes

Exposure to the same cancer-causing damage does not always produce the same result, and new research suggests inherited genetic differences may help explain why.

A study published in the journal Nature on Wednesday, found that genetic background can influence how tumors form and evolve after DNA damage, providing new clues into why similar environmental risks may lead to different cancer outcomes.

Researchers from the University of Cambridge, the University of Edinburgh and other institutions studied how inherited differences affected cancer development by using four strains of mice with different genetic backgrounds.

The mice were exposed to the same dose of diethylnitrosamine (DEN), a chemical known to damage DNA and trigger liver tumors. Because the animals received the same exposure under controlled conditions, scientists were able to examine the role of genetic differences while reducing the influence of environmental factors.

The research team analyzed the genomes of nearly 600 tumors and compared how cancers developed across the different mouse strains.

They found that while tumors often reached similar biological outcomes, the path they followed was influenced by the animals’ genetic background. Inherited differences affected which cancer-driving mutations appeared and how tumors changed over time.

Across the mouse strains, cancers frequently developed changes involving the MAPK pathway, a network of signals that regulates important processes such as cell growth and is commonly involved in many types of cancer. However, researchers found that genetic background influenced additional changes that shaped tumor development.

“Cancer does not arise entirely by chance,” said Duncan Odom, a senior author of the study who led the research while at the Cancer Research UK Cambridge Institute and is now based at the German Cancer Research Centre. He said tumors may reach similar biological endpoints, but the route they take can be influenced by an individual’s genetic background.

Scientists have long known that factors such as smoking, ultraviolet radiation and other environmental exposures can damage DNA and increase cancer risk. However, people exposed to similar risks do not always develop cancer, while some people with no clear exposure history still develop the disease.

The researchers said the findings could eventually help improve cancer screening and treatment strategies by taking inherited genetic differences into account. They noted, however, that more research is needed to understand how these findings apply to humans.

Sarah Aitken, the study’s first author, said inherited genetics and population diversity may need to be considered in future approaches to cancer prevention and treatment.

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