Study finds inherited genes steer how DNA damage becomes cancer

A sweeping international study published in Nature on July 22 has provided the first direct evidence that a person's inherited genetic makeup can determine how DNA damage from environmental exposures leads to cancer — and how that cancer evolves over time.news-medical+2

The research, conducted in mice by teams at the University of Cambridge, the University of Edinburgh, Yale School of Medicine, and the German Cancer Research Center (DKFZ) in Heidelberg, offers a potential answer to a longstanding puzzle: why most smokers never develop lung cancer, while some non-smokers do.eurekalert+1

A Tightly Controlled Experiment

The researchers administered a single dose of a liver carcinogen called diethylnitrosamine — a chemical found in tobacco smoke and some processed foods — to four genetically distinct strains of mice, all at the same age and under identical conditions. They then sequenced the genomes of 581 resulting tumors, analyzed gene activity, and reconstructed each tumor's evolutionary path.news.yale+1

By holding environmental factors constant, the team was able to isolate the role of inherited genetics in a way that human studies, complicated by differences in lifestyle and exposure history, have struggled to achieve.news-medical+1

Same Chemical, Different Cancers

Across all strains, tumors nearly always activated the same cancer-promoting signaling system, known as the MAPK pathway. But the specific driver mutations acquired, the stability of the tumor genome, and the speed of cancer development all varied depending on each mouse's genetic background.news-medical+2

"Cancer does not arise entirely by chance," said Duncan Odom, who co-led the study. "Although tumors often reach the same biological endpoint, the path to that endpoint is determined by an individual's genetic background".news-medical

"Exactly the same mutation can have an opposite effect in different individuals," added co-lead author Sarah Aitken, assistant professor of pathology at Yale School of Medicine.news.yale

Implications for Cancer Screening and Treatment

The findings suggest that screening programs, which currently target groups by age or known exposures like smoking, may need to incorporate inherited genetics. "We don't consider people's genetics in the equation. This research indicates that perhaps we should," Aitken said.news.yale

The study also raises the possibility that responses to DNA-damaging cancer treatments could differ depending on a patient's background genetics, strengthening the case for more personalized approaches to therapy. The research was funded by Cancer Research UK, the Medical Research Council, the European Research Council, and Wellcome.sciencedaily+1