Discipline: Biological Sciences
Subcategory: Cancer Research
Harvey S. Salley, Jr. - Clark Atlanta University
Co-Author(s): Maxine S. Harlemon and Nathan J. Bowen, Center for Cancer Research and Therapeutic Development, Clark Atlanta University
Cancer incidence rates differ between different tissue types. For example, the prostate gland has a much higher cancer incidence rate than the neighboring bulbourethral gland. Recently, Tomasetti and Vogelstein have proposed a hypothesis to explain this observation. They present data indicating that in tissues where resident stem cells replicate more frequently, higher cancer incidence rates follow. That is, tissues with higher cellular turnover have higher cancer incidence rates. They further explain that the more cells replicate, the higher the chance of them gaining mutation through the mistakes that occur in the replication of DNA. Cancer incidence rates also differ between ethnic groups. African American men have an increased incidence rate of prostate cancer when compared to their European American and Asian American counterparts. This increased risk may in part be due to heritable genetic factors since prostate cancer has an overall heritability rate of 58%. To address the possible cause of this health disparity, we present the following hypothesis that builds on the logic of Tomasetti and Vogelstein. We hypothesize that the difference in prostate cancer incidence rates between individuals with relatively recently differing geographical origins is due to a difference in mutation rates in the cells of origin of prostate cancer. We present our working model including the concept that men of recent African origin have slightly higher levels of reactive oxygen species, ROS, in their circulatory system. Our model posits that slightly higher steady-state levels of ROS evolved in humans in a pro-immunological response to blood-born pathogens. H2O2 and related ROS are strong oxidizing agents that can react with pathogen derived proteins and degrade their function and inhibit pathogen replication. However, ROS are also known to cause mutations to DNA by oxidative damage. This unintended consequence of the selection for higher H2O2 levels for protection against pathogens has led to a slightly higher mutation rate in the human host, leading to the differences in prostate cancer incidence rates that are observed. We further hypothesize that early humans migrating out of Africa (OOA) were geographically isolated and had less exposure to blood-born pathogens. The OOA migration then led to relaxed negative selection on factors producing or removing H2O2 from blood. Lower ROS levels in the blood consequentially reduced the mutation rate to adult prostate tissue stem cells leading to a lower incidence rate of prostate cancer. We will present data implicating melanin, ultraviolet light (UV) and the antioxidant pathway regulated by the NFE2L2 (NRF2) gene in the evolution of these differences. We also present data indicating that genetic differences found within the coding region of ZIC2, another gene possibly involved in the regulation of oxidative stress, are variable between geographically isolated populations and that these polymorphisms may contribute to different prostate cancer incidence rates.
Funder Acknowledgement(s): The authors were supported in part by the NSF Award #1305041 and NIMHD grant 2G12MD007590-27A1.
Faculty Advisor: Nathan Bowen, email@example.com
Role: Literature review and assisting with data analysis.