Abstract CN02-02: Elucidating mechanisms of environmentally induced kidney cancers

Epidemiology data suggests that exposure to trichloroethylene (TCE) is associated with increased susceptibility to a variety of diseases including elevated incidence of kidney cancer. Molecular analysis of kidney cancers from workers in Germany revealed a TCE-specific hotspot mutation in the von Hippel-Lindau (VHL) gene. We used a mouse embryonic stem cell assay to demonstrate that the TCE-associated VHL mutation is highly transforming and confers apoptotic and DNA damage resistance. To investigate genetic susceptibility to TCE, we exposed a genetically diverse mouse population to TCE with or without inorganic arsenic (iAS), a toxicant naturally found in the environment in many locations. We observed cooperation between TCE and iAS in the induction of a gene expression signature in kidneys identical to that caused by the TCE-associated VHL mutation. After one year of exposure, subsets of mice developed kidney cancers, some of which became metastatic to the lung. A systems analysis revealed complex patterns of genetic susceptibility. The results demonstrate that chemical combinations can elicit additive and synergistic toxicities in genetically susceptible individuals. Citation Format: David Threadgill. Elucidating mechanisms of environmentally induced kidney cancers. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr CN02-02.