Scientists Uncover Genetic Clues Behind Lung Cancer Risk in Smokers and Non-Smokers - Video

Genes may determine how much DNA damage smoking and other exposures cause, study finds

A new study has provided the first direct evidence that a person's inherited genes can influence how much DNA damage builds up after exposure to cancer-causing agents such as cigarette smoke or sunlight. The findings may help explain why some lifelong smokers never develop lung cancer, while some non-smokers do.

The research, published in Nature, suggests that inherited genetic differences shape not only the risk of developing cancer but also how cancers evolve after DNA damage occurs.

To investigate this, researchers bred four genetically distinct strains of mice with different natural susceptibilities to liver cancer. The animals represented a level of genetic diversity similar to that seen in humans.

Each mouse received the same dose of the cancer-causing chemical diethylnitrosamine (DEN) at 15 days of age. DEN is found in tobacco smoke and certain processed foods and is known to damage DNA in liver cells.

Because every mouse experienced identical exposure under controlled conditions, researchers were able to eliminate lifestyle and environmental differences that often make human studies difficult to interpret.

The team then analyzed nearly 600 liver tumors, sequencing their genomes and studying gene activity to reconstruct how each cancer developed.

They found that tumors across all mouse strains almost always developed mutations that activated the MAPK signaling pathway, a key driver of cell growth and many cancers.

However, genetic background strongly influenced what happened next. Depending on the inherited genes of each mouse, tumors accumulated different patterns of mutations, activated additional cancer-related pathways, and often developed whole-genome duplication—a process in which cells gain an extra copy of all their chromosomes, creating additional genetic material that can acquire further mutations.

Although the study was conducted in mice, the results suggest that inherited genetic differences could play an important role in determining individual cancer risk in humans.

REFERENCE: Aitken, S.J., Connor, F., Feig, C. et al. Genetic background sets the trajectory of experimental cancer evolution. Nature (2026). https://doi.org/10.1038/s41586-026-10821-z