Background: Renal medullary carcinoma (RMC) is a rare but deadly cancer that almost always occurs in young African-Americans, more often in the right kidney (~70% of cases) than the left. All individuals with RMC have either sickle cell disease, sickle cell trait, or other conditions associated with sickling of red blood cells. Individuals with sickle cell trait frequently have no other clinical symptoms and often learn that they harbor the sickle cell trait after being diagnosed with RMC. Less than 5% of patients with RMC will survive beyond 5 years after diagnosis, despite the best currently available therapies. We need to understand how and why RMC occurs in order to develop strategies to more effectively prevent, diagnose, and treat this highly lethal kidney malignancy.

Hypothesis/Objective: To this day, we do not know why RMC only occurs in individuals with sickle cell disease or trait, or why it arises more frequently in the right kidney. To address these questions we propose a novel, testable concept that connects these two defining characteristics of RMC. The renal inner medulla is the least oxygenated tissue in the human body. It also contains the highest concentration of salt. This high amount of salt damages the DNA of cells in the renal inner medulla and, at the same time, suppresses the repair of this damage. In addition, the low oxygen levels and high salt concentrations will force the red blood cells of individuals with sickle cell trait or disease to change their shape, a phenomenon known as "sickling." Red blood cells that have "sickled" can obstruct the blood supply of the renal inner medulla resulting in tissue death ("microinfarcts"). These microinfarcts reduce the salt concentration in the renal inner medulla, thus activating the repair of DNA damage. However, because of the low oxygen concentration in these tissues, the repair of DNA will be suboptimal and have increased chances of introducing mutations that can lead to cancer. The physical laws governing fluid circulation stipulate that longer blood vessels will result in lower blood flow. The right kidney artery is known to be longer than the left and this may result in reduced blood flow on the right side, thus increasing the chances that microinfarcts can happen on the right renal inner medulla compared with the left.

Based on the above considerations, we propose that the microinfarcts in the renal inner medulla, resulting from sickling of red blood cells, will be more commonly found in the right kidney and will produce tissue damage that will activate a suboptimal repair of DNA, thus increasing the chances that cells will mutate to cancer. To test this concept, we propose the following experiments in mice genetically engineered to mimic human sickle cell disease or trait:

* Determine if microinfarcts are more common in the right renal inner medulla compared with the left.

* Determine if there is increased activity of suboptimal DNA repair mechanisms in the renal inner medulla of mice mimicking human sickle cell disease and trait compared with mice mimicking normal human blood circulation.

Impact: RMC most frequently occurs in a particularly vulnerable population consisting mainly of young African Americans. Following its validation by the above experiments, we intend to use the proposed model to investigate how environmental factors and genetic or epigenetic variations can increase or reduce the risk of developing RMC. These insights can help us develop strategies to effectively screen and prevent RMC.

Innovation: The concept we propose is the first to model how and why RMC happens in individuals with sickle cell trait or disease. Our proposed experiments will allow us to determine if anatomical differences in kidney blood supply can explain this laterality. After we complete this project, we plan to use our experience with these models to develop new strains of mice genetically engineered not only to mimic human sickle cell trait and disease but also to harbor the genetic mutation that is found in all RMCs, in a gene called SMARCB1. This will allow us to explore how microinfarcts due to sickle cell disease or trait interact with SMARCB1 genetic mutations, and to identify additional factors that drive the development of RMC.