Inherited genetic background played a major role in determining how liver cancers developed in a controlled mouse model, according to a study published in Nature. Researchers found that genetically distinct mouse strains developed tumors differently despite receiving the same carcinogen under identical laboratory conditions. The findings suggest that inherited genetic variation can influence cancer evolution from its earliest stages.
The investigators induced liver tumors in four genetically distinct mouse strains using a single exposure to diethylnitrosamine. They then analyzed 581 tumors using whole-genome sequencing, RNA sequencing, and histopathology, allowing them to compare tumor evolution while controlling for environmental factors.
The mice differed markedly in how quickly tumors developed. Tumors appeared after 25 weeks in the most susceptible strain but took up to 78 weeks in the most resistant strain. These differences were also reflected in the rate of spontaneous liver tumors, suggesting that inherited genetics influenced baseline cancer susceptibility.
Genetic background also affected the biology of the tumors. Different strains showed distinct patterns of mutation burden, chromosomal instability, whole-genome duplication, and copy number alterations. However, nearly all tumors acquired activating mutations in the same signaling pathway – the mitogen-activated protein kinase (MAPK) pathway. The specific driver genes selected, including BRAF, HRAS, EGFR, and KRAS, varied between strains, indicating that inherited genetics influenced which mutations provided the greatest selective advantage during tumor development.
RNA sequencing showed that although MAPK pathway activation produced many common transcriptional changes, inherited genetic background modified downstream cellular responses involving p53, transforming growth factor beta (TGF-beta), and peroxisome proliferator-activated receptor signaling. These interactions suggest that the biological effects of the same driver mutation can differ depending on the host genome.
The researchers also found differences in the earliest stages of tumor evolution. Tumors arising in the most susceptible strain often developed after fewer evolutionary steps, whereas tumors in other strains required additional genetic changes before expanding.
Although the work was performed in an experimental mouse model, the researchers said the findings may help explain why cancers in different populations can vary in susceptibility, driver mutations, and evolutionary patterns. They suggested that inherited genetic background may be an important consideration alongside somatic mutations when studying cancer biology and interpreting genomic data.
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