Scientists have found the first direct evidence of the powerful role our genetic makeup plays in influencing our risk of cancer, with inherited genes interacting with acquired genetic mutations to shape how tumours evolve.

The findings could explain why some people are more susceptible to cancer than others in the same environment and suggest that future cancer prevention and screening strategies may need to account more carefully for inherited genetics and population diversity.

The research, published today in Nature and carried out in mice, suggests that responses to DNA-damaging cancer treatments could differ depending on a patient's background genetics, strengthening the case for a more personalised approach to treatment.

Tumours arise when our DNA accumulates errors, or mutations, causing the cells to grow faster and ignore signals that would otherwise instruct damaged cells to die before they can cause harm. Environmental exposures – for example, cigarette smoke or sunlight – influence how much DNA damage occurs, and inherited genetic alterations can alter how many mutations accumulate.

Not everyone exposed to the same environmental risk factors will develop cancer, however. Most smokers do not develop lung cancer – and some non-smokers develop lung cancer. The reason why is almost certainly related to our inherited genetic makeup, but finding direct evidence has proved challenging in patient cohort studies. Even though many studies have suggested that inherited genetic differences affect cancer risk, proving this link has been difficult because individuals within – and between – human populations vary in lifestyle, environment, and exposure history.

The study is the result of years of international collaboration, between the University of Cambridge, University of Edinburgh, and others around Europe and the US, and was co-led by Professor Duncan Odom, Dr Sarah Aitken, and Professor Martin Taylor. 

In experiments largely carried out at the Cancer Research UK (CRUK) Cambridge Institute at the University of Cambridge, scientists developed an experimental approach that allowed them to control environmental factors experimentally and show that genetic background itself can alter how tumours arise and evolve.

The team bred four strains of mice with varying susceptibility to liver cancer, spanning a level of genetic diversity comparable to that seen in human populations. They then exposed the mice to a single dose of the liver carcinogen diethylnitrosamine (DEN). DEN is found in tobacco smoke and some processed foods and is known to cause DNA damage in liver cells, leading to mutations that can initiate tumour growth. 

Because every mouse received the same dose at the same age – 15 days of age – under controlled conditions, the researchers were able to eliminate the environmental variation that confounds studies in humans.

They then sequenced the genomes of almost 600 tumours and analysed the gene activity that developed as well as examining the untreated mice to compare spontaneous tumour formation across strains. Using this data, they were able to reconstruct how each tumour evolved from its original cancer-causing mutation.

Across all mouse strains, cancers nearly always acquired a cancer-driving mutation that activated the same cancer-promoting signalling system, called the MAPK pathway. This is a multi-step cascade of molecular signals that controls important life processes, including cell growth and cell differentiation, and plays a key role in numerous types of cancer.

However, depending on the inherited genetics of the mouse, the particular driver mutation that was acquired altered the activity of other cancer-associated signalling pathways, as well as causing a striking tendency for whole-genome duplication, an event in which the entire set of chromosomes is doubled.

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 tumours 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 tumour development.”

The researchers say the findings have implications for cancer screening and precision medicine.

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 tumours, 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.”

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

The University of Cambridge and Addenbrooke's Charitable Trust (ACT) are fundraising for Cambridge Cancer Research Hospital, a new hospital that will transform how we diagnose and treat cancer, with early detection at the heart of its mission. Set to be built on the Cambridge Biomedical Campus, the hospital will bring together clinical excellence from Addenbrooke’s Hospital and world-leading researchers at the University of Cambridge. The research carried out there aims to change the lives of cancer patients across the UK and beyond. Find out more here.

Reference

Aitken, SJ et al. Genetic background sets the trajectory of experimental cancer evolution. Nature; 22 July 2026; DOI: 10.1038/s41586-026-10821-z