The MexTAg Collaborative Cross: Understanding Genetic Modifiers in Mesothelioma
Abstract
The Peer Reviewed Cancer Research Program Topic and Military Relevance Focus Area to be addressed is mesothelioma caused by the environmental carcinogen asbestos. This research project aims to identify genes that are associated with the development of mesothelioma following asbestos exposure. Mesothelioma is an incurable cancer caused by asbestos. It usually occurs in the lungs after breathing in asbestos-containing dust. Typically, people are exposed in a work environment where they are either involved in the production, processing, or use of asbestos-containing materials in a way that liberates dust. There is strong evidence that a person’s genes have a powerful effect on their chance of contracting mesothelioma, but the genes involved have not been identified. In other diseases, you can find susceptibility genes if you have a large, well-characterized group of patients to compare with a similar group of people who don’t have the disease, despite same levels of exposure to the disease-causing agent. Unfortunately, human studies that have attempted to identify mesothelioma susceptibility genes have had little success; this is mostly because they are based on relatively small study populations, and the data are further hindered by additional complicating factors such as different amounts of asbestos exposure and the effect of different smoking and diet histories between cases and control groups. Because mesothelioma generally occurs in older people, sometimes 30-40 years after they breathed in asbestos, we can never be sure that someone in the control group who doesn’t have the disease is not going to get the disease in the future. For all these reasons, human studies have detected only a few genes and these have only a minor impact on mesothelioma risk. We know that animals that are exposed to asbestos have a similar chance of developing mesothelioma as humans, and the disease looks exactly the same in the lungs of animals and humans. Mice share approximately 97% of their genes with humans. We therefore have the opportunity to overcome the problems inherent to human studies and discover genes that can prevent or delay mesothelioma in mice by combining two unique mouse models. One is a powerful genetic resource called the “Collaborative Cross” (CC) that can rapidly identify susceptibility and resistance genes with unprecedented accuracy. The second is a well-characterized mouse model where a genetic accelerator means that all mice develop mesothelioma following asbestos exposure. We will combine these models so that we can rapidly identify genes associated with mesothelioma resistance and susceptibility. These results will be confirmed against large human mesothelioma patient genetic datasets. There has been no significant advance in the treatment of mesothelioma over the last decade, and the development of new treatment options for mesothelioma patients is limited. Understanding the key biological pathways associated mesothelioma development or resistance is absolutely crucial to be able to provide the foundation for the development of new therapeutic options. Our approach encompasses more genetic variation than any planned or previous study into this disease and is likely to be significantly faster and cheaper than current human genetic screening methods. The genes we find will significantly advance the field of mesothelioma treatment and research in a number of different ways. The benefits of such knowledge will enable the development of new or improved treatments by targeting previously unknown biological pathways associated with mesothelioma development or resistance. Additionally, such information may help identify individuals with a high likelihood of developing disease following asbestos exposure so that they can be screened more regularly. Such tests would identify the most at-risk patients for further treatment, while reassuring remaining asbestos-exposed individuals that mesothelioma is
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810343
Entities
People
- Richard Lake
Organizations
- United States Army
- University of Western Australia