Genetic background influences cancer risk

Researchers from Yale Cancer Center, the University of Cambridge and collaborators published a Nature paper reporting that inherited genetic differences shape how the body repairs DNA damage from smoking. In mouse models, a susceptible strain (C3H) developed liver tumours after a single driver mutation, whereas a resistant strain (CAROLI) required multiple mutations, delaying tumour onset and sometimes preventing cancer. The authors suggested that these findings could explain why only a minority of lifelong smokers develop lung cancer and hinted at future personalised prevention through genetic screening.

A few days later, the same research team provided deeper mechanistic insight by sequencing nearly 600 liver tumours from four inbred mouse strains exposed to the carcinogen diethylnitrosamine. The analysis confirmed that germline genetic makeup dictated which driver genes were mutated (e.g., Braf, Hras, Egfr, Kras), the speed of tumour development, and the occurrence of whole‑genome duplication. Susceptible strains needed only a single driver event, often with Braf mutations and genome doubling, while resistant strains required multiple hits and showed greater early sub‑clonal loss. The follow‑up emphasized a strong germline‑somatic epistatic interaction, reinforcing the original claim that host genetics can profoundly influence cancer risk even under identical environmental exposures.