Genetic Background Influences Cancer Development and Mutation Patterns, New Study Finds

A recent study published in Nature reveals that inherited genetic differences significantly affect not only the risk of developing cancer but also the mutation patterns and evolutionary pathways tumors follow after DNA damage. The research helps explain why some smokers develop lung cancer while others do not, and why some people who never smoked still get the disease. Similar variability is seen in skin cancer risk from sun exposure.

Dr. Avishay Spitzer, a medical oncologist and cancer genomics expert at Ichilov Medical Center, explains that while mutations accumulate naturally in healthy tissues, most mutated cells do not become tumors. The study focused on how moderate genetic variation across the genome influences which mutations persist in tumor cells, how many mutations are needed to initiate cancer, and the tumor’s developmental trajectory.

The researchers conducted controlled experiments on 215 male mice from four genetically distinct groups, exposing them to the carcinogen diethylnitrosamine (DEN), which damages liver cell DNA. Despite identical exposure conditions, tumor development rates varied widely: tumors appeared as early as 25 weeks in the most susceptible group and only after 78 weeks in the most resistant group. Similar patterns were observed in spontaneous tumor formation without DEN exposure.

Analysis of 581 liver tumors showed that although 95% activated the same biological pathway (MAPK), they did so via different mutations in genes like Braf, Hras, Egfr, or Kras. The genetic background influenced which mutations conferred growth advantages and how many mutations were required to start tumor growth. The most sensitive group often needed only one driver mutation, while others required two or more. Differences were also found in DNA repair gene activity and chromosomal stability.

The study suggests that inherited DNA acts as an evolutionary rulebook determining whether mutated cells are eliminated, remain dormant, or progress to malignancy. This insight could impact cancer risk assessment, early detection, and personalized treatment strategies by integrating a patient’s full inherited genome with tumor genetics. However, further research is needed to confirm these findings in humans and translate them into clinical practice.