Study reveals inherited genetics shape cancer risk and tumor evolution

Why do some people who smoke never develop lung cancer, while others who never touch a cigarette do? Scientists have long suspected the answer lies in our inherited genes, but proving it has been nearly impossible. Now, an international team has produced the first direct evidence that our genetic makeup fundamentally shapes both our cancer risk and the way tumors evolve once they begin to grow.

The research, published in Nature and conducted across mouse populations, reveals that inherited genetics don't simply make us more or less vulnerable to cancer in isolation. Instead, they interact with the mutations that accumulate in our cells over time, steering tumors down different developmental paths even when the initial trigger is identical. The finding emerged from years of collaboration between scientists at the University of Cambridge, University of Edinburgh, and institutions across Europe and the United States, led by Professor Duncan Odom, Dr. Sarah Aitken, and Professor Martin Taylor.

The challenge in studying this question in humans is overwhelming. People differ not just in their genes but in their lifestyles, environments, and exposure histories. A smoker who develops lung cancer might have been exposed to secondhand smoke as a child, worked in a polluted factory, or lived in a city with poor air quality. Teasing apart which differences matter—and how much—is nearly impossible. The researchers solved this by turning to mice. They bred four strains with varying susceptibility to liver cancer, chosen to reflect the genetic diversity seen in human populations. Then they exposed every mouse to a single dose of diethylnitrosamine, a liver carcinogen found in tobacco smoke and some processed foods, at exactly the same age under identical conditions. This eliminated the environmental noise that confounds human studies.

The team sequenced the genomes of nearly 600 tumors that developed and analyzed the gene activity within them, reconstructing how each cancer evolved from its initial mutation. What they found was striking: across all the mouse strains, tumors nearly always acquired a mutation that activated the same cancer-promoting signaling system, called the MAPK pathway. This cascade of molecular signals controls cell growth and cell differentiation and is implicated in many human cancers. But here was the crucial difference. Depending on the inherited genetics of each mouse, the particular driver mutation that appeared altered the activity of other cancer-associated pathways in distinct ways. Some genetic backgrounds showed a striking tendency toward whole-genome duplication, an event in which the entire set of chromosomes is doubled.

Odom explained the significance: cancer does not arise by pure chance. Although tumors often reach the same biological endpoint, the path to that endpoint is determined by an individual's genetic background. For the first time, the researchers had shown the extent to which inherited genetics influences both the mutation processes and the pathways leading to tumor development. The implications ripple outward. If genetic background shapes both cancer risk and how tumors evolve, then future screening and prevention strategies will need to account for inherited genetics and population diversity in ways they currently do not. Equally important, how people respond to cancer drugs is likely to differ depending on their inherited genetics, suggesting that diagnostics and treatments may need to be tailored accordingly.

Dr. Sarah Aitken, now an assistant professor at Yale School of Medicine, emphasized that the findings point toward precision medicine—the idea that treatment should be customized to each patient's genetic profile. The research was funded primarily by Cancer Research UK, the Medical Research Council, the European Research Council, and Wellcome. While the work was conducted in mice, the researchers acknowledge that more research is needed to understand what these findings mean for human cancer. But the door has opened. This study suggests that our inherited genes might have far greater influence on how cancers develop after DNA damage than previously understood, potentially reshaping how we prevent, screen for, and treat the disease.