Inherited genetic differences can influence not only whether cancer develops after DNA damage but also which evolutionary route a tumour follows, according to research highlighted by the University of Cambridge on Monday. The peer-reviewed Nature study used a controlled liver-cancer model in mice and found that genetic background was strongly associated with mutation selection, tumour growth and susceptibility.
The international team, co-led by Sarah Aitken, Duncan Odom and Martin Taylor, sought to separate inherited effects from lifestyle and environmental differences that complicate studies in people. Researchers used four genetically distinct mouse strains whose combined diversity was comparable to variation across human populations, while controlling sex, living conditions and exposure to a carcinogen.
Each mouse received the same dose of diethylnitrosamine at 15 days old. The chemical damages liver-cell DNA and is also found in tobacco smoke and some processed foods. The team sequenced nearly 600 tumours, measured gene activity, examined tissue and compared untreated animals, allowing it to reconstruct early tumour development hundreds of times under matched conditions.
Tumours across the strains almost always acquired a driver mutation activating the cancer-linked MAPK signalling pathway, but the preferred driver gene and precise mutation differed by inherited background. The paper also found strain-specific patterns in whole-genome duplication and early subclone survival. In the most susceptible strain, C3H, one driver mutation frequently supported transformation, while other strains typically required at least two driver events.
The authors said the results show interactions between inherited, or germline, variants and mutations acquired in cells can alter the selection pressures that shape a tumour. They argue that genetic background deserves consideration alongside environmental exposure and tumour mutations when researchers design cancer studies and interpret their results, especially when study populations lack genetic diversity.
The findings do not establish a new test or treatment for patients. The experiments involved mice exposed to a liver carcinogen, and researchers said further work must determine how closely the patterns apply to human cancers. If human studies confirm the effect, inherited diversity could eventually improve risk assessment, screening design and understanding of why responses to cancer drugs vary.
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