Inherited genetic background influenced how liver tumors developed in a controlled mouse model, affecting which driver mutations emerged, how stable tumor genomes remained, and how cancers evolved over time. The findings suggest that germline variation may shape tumor evolution independently of environmental exposures, providing context for the interpretation of molecular profiling in cancer diagnostics.
Published in Nature, the researchers induced liver tumors in four genetically distinct inbred mouse strains exposed to the same carcinogen under identical experimental conditions. They analyzed 581 tumors using histopathology, whole-genome sequencing, and transcriptomic profiling, allowing them to isolate the effects of inherited genetic background on tumor development.
The different mouse strains showed marked differences in cancer susceptibility, with tumors developing earlier in some strains than others. Despite these differences, nearly all tumors acquired activating mutations in the mitogen-activated protein kinase (MAPK) pathway, most commonly involving Braf, Hras, Egfr, or Kras.
However, the specific driver mutations selected varied according to genetic background. These differences were not explained by mutation rates or DNA sequence alone, indicating that inherited genetic variation influenced which somatic mutations provided a selective advantage during tumor development.
Genetic background also affected genomic stability. One strain showed a much higher frequency of early whole-genome duplication, accompanied by increased aneuploidy and copy number alterations. In addition, tumors arising in the most susceptible strain typically required fewer detectable driver mutations and transformed earlier than tumors in the other strains, suggesting differences in the threshold for malignant transformation.
Transcriptomic analysis showed that tumors shared a common MAPK-driven gene expression program across all strains. However, the downstream effects of the same driver mutation differed according to genetic background, particularly in pathways involving p53, transforming growth factor beta (TGF-beta), and peroxisome proliferator-activated receptor (PPAR) signaling. These findings suggest that identical driver mutations may have different biological consequences depending on the inherited genome.
The study provides experimental evidence that germline genetic variation can influence not only cancer risk but also the genomic alterations detected during tumor profiling. Although the work was performed in mice, it offers a framework for understanding why driver mutation frequencies and patterns of tumor evolution may differ across populations, an important consideration as molecular diagnostics become increasingly integrated into cancer classification and precision oncology.
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