Genomic bases for African geo-ethnic prostate cancer health disparity - With no known cause or modifiable risk factor, prostate cancer (PCa) is characterized by significant geo-ancestral disparity. Men of African ancestry and/or from Africa are at greatest risk for aggressive disease. African American men are at 2.5-to-5-fold increased risk for lethality. Here we will address if this geo-ancestral disparity is driven by ancestry (genetics), geography (environment), or a combination (gene x environment). Our approach is to use the power of whole tumor/blood genome interrogation to identify contributing genetic and non-genetic factors. Genetic factors include from inherited rare pathogenic mutations to tissue acquired cancer drivers. Conversely, non-genetic factors such as environmental carcinogens, leave a computationally derived pattern of somatic variants (mutational signatures) in the developing tumor. Additionally, the mostly discarded non-human prostate genomic data holds unmet potential to identify contributing pathogens (bacterial or viruses) to a cancer featured by chronic inflammation. However, geo-ancestrally representative PCa whole genome data is lacking. Here, this team is creating a uniquely geo-ancestral representative PCa genomic resource (700 cases) to tackle three specific aims, to identify ancestry specific inherited risk factors, to identify acquired genomic events driving geo-ancestral disparities, while alluding to yet unknown contributing environmental (non-genetic) factors, and to identify if pathogenic microbes are contributing (at least in part) to aggressive disease. Our geo-ancestral resource, derived from the greater Chicago region and Brazil, with a focus on those most impacted, men with African ancestral heritage against a backdrop of non-African ancestry, while distinct geographies provide for environmental comparative analyses. The data generated, will be further compared with geographically distinct resources from Africa, Australia and Europe. The rationale for this study is built on this team providing in 2022 tantalizing evidence for geographically distinct prostate tumor genome scars, which suggested for a potential environmental risk factor at play. Identifying such a risk factor requires globally inclusive data. A disease of unknown etiology, identifying the underlying causes (genetic and non-genetic) of PCa health disparities has significant implications for advancing our biological understanding, while directly facilitating early detection, prevention, and ultimately treatment for lethal disease.
