Genetic Background Shapes Cancer Evolution and Tumor Progression

This study examined how inherited genetics influence the progression and evolution of cancer. The researchers used an experimental system involving wild-type inbred mouse strains to explore how genetic background affects tumor development, focusing on liver cancer induced by a chemical mutagen.

Understanding how genetic background shapes cancer evolution is crucial for improving cancer prevention, diagnosis, and treatment strategies. Human studies on this topic are challenging because each patient has a unique combination of genetic and environmental exposures. This research provides insights into how inherited genetic differences impact cancer risk, tumor progression, and the selection of genetic mutations during cancer development, which could inform personalized medicine approaches and improve clinical outcomes.

The researchers induced liver cancer in male mice from four genetically distinct strains by exposing them to diethylnitrosamine (DEN), a chemical known to cause DNA damage. Tumors were collected and analyzed over several months. They used whole-genome sequencing, RNA sequencing, and histopathological analysis to examine genetic mutations, gene expression patterns, and tumor characteristics. Environmental factors like diet and housing were controlled in the study to isolate the effects of genetic variation.

The study found that genetic background significantly influenced cancer susceptibility, tumor latency (time to tumor development), and the types of mutations driving cancer progression. For example, some strains were more prone to early tumor development, while others showed delayed progression. All strains showed a preference for mutations in MAPK pathway genes, but the specific mutations and their frequencies varied between strains. Unexpectedly, inherited (germline) genetics interacted with acquired (somatic) driver mutations and changed expression of other cancer-related pathways, such as p53 signaling, and also the occurrence of whole-genome duplication, a process linked to genome instability.

This research was supported by the Cancer Research UK Cambridge Institute core award (20412) and MRC Toxicology Unit core funding programme grants (RG94521 and MC_PC_24012). Additional support came from MRC Human Genetics Unit core funding programme grants (MC_UU_00007/11, MC_UU_00007/16, MC_UU_00035/1, and MC_UU_00035/2), as well as European Molecular Biology Laboratory core funding. The study also received funding from the Cancer Research UK strategic award (22398), Wellcome Trust (WT108749/Z/15/Z, WT202878/B/16/Z, and 202878/Z/16/Z), the Spanish Ministry of Science (PID2021-126568OB-I00), and ERC (615584 and 788937). Funding support was also provided by the Helmholtz Society (DKFZ abteilung B270) and the Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Science, Innovation and Universities. S.J.A. was supported by a Wellcome Trust PhD Training Fellowship for Clinicians (WT106563/Z/14/Z and WT106563/Z/14/A), National Institute for Health Research Clinical Lectureship and CRUK Clinician Scientist Fellowship (RCCCSF-May23/100001). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other grantors. Yale University also provided funding and support for this research.