Genetics of Susceptibility and Risk Research
The variety of inbred, recombinant inbred, diversity outbred, congenic, consomic, and advanced intercross mouse strains are effective tools to discover and define the genetic and environmental determinants of cancer susceptibility, and refine these discoveries to develop markers for assessment of risk of developing cancer, having progressing metastatic tumors, and responding to therapy or having recurrent cancer. Integrative cancer genetics projects are combining many of these resources to elucidate more details of these cancerous situations. Some projects in this arena will resemble a mouse "personal cancer genetics" strategy to learn as much as possible about these useful animals.
Mouse models for many important single high-risk alleles in genes resulting in oncogenic situations have been hugely informative for our understanding of many aspects of cellular function and malfunction, but it is clear from human studies that these types of aberrant genes represent only a fraction of clinical cancer occurrences. Polygenic effects from various susceptibility genes will represent many more cases of human cancers. Mouse models are increasingly available to approach these complex and challenging types of investigations.
Examples of studies that indicate differing susceptibility to development of cancer vary widely. One example of skin cancer research found that some mice were naturally resistant, and others would develop the tumors following a chemical challenge. This leads researchers to genomic regions that they investigate in more detail. Insights about pancreatic cancer risks are provided by multiple mouse models. Lung cancer has been extensively studied, and switches from resistance to susceptibility have been identified using mutant mice. Other mice that were susceptible to spontaneous tumors have provided further leads. A chromosome substitution strain study teaches us more about possible mechanisms as well. Crosses of inbred mice generate candidate regions for colon cancer. Mice have even provided surprising awareness of gender differences in susceptibility that may be important in breast cancer and also in liver cancer.
Large and complex studies are now possible with high-throughput technologies. One example using cross-species comparative genomics yielded novel cancer genes using both human cells and mouse tumors. Similarly, large scale pursuits of environmental epigenomics factors employing mouse models and cross-species comparisons will deliver new knowledge.
Intriguing research on risk factors, paired with susceptible mouse models, can provide informative directions for additional studies. The role of diet in inducing hepatocellular carcinoma has been examined in mouse models. Radiation exposure can be investigated in mice, and has been used to identify loci that may play roles in the development of cancer. Large-scale studies of environmental impacts using mouse models are being performed and will likely influence our understanding of risk factors on many fronts.