High-Risk Prostate Cancer in Southern Africa: Unravelling the Genome and Exposome (TARGET Africa)
Abstract
Prostate cancer (PCa) is characterized by significant geographic and ethnic disparity. While incidence rates are highest in Australia, Europe, and Northern America, Africa has the highest mortality rates. This is particularly significant in southern Africa, where a man has a 3.5 times higher risk of dying from PCa compared to the global average. A disease of older age, this is further alarming when considering the 20-year decrease in overall life expectancy in southern Africa compared with non-African countries. In the United States, being African American increases a man’s risk for a PCa associated mortality 2.3 times for men 65 years and older and 3.1 times for men younger than 65 years. African ancestry is a significant risk factor for lethal PCa. Although classified as high-risk, studies within Africa have been missing or limited. The overarching goal for the TARGET Africa proposal is to reduce lethal PCa in men of African ancestry by identifying the factors (environmental, lifestyle, and molecular-genetic) contributing to aggressive PCa in men from Africa, with a focus on underserved rural communities. As such, this proposal directly addresses a FY20 PCRP Overarching Challenge. To achieve our goal, the Southern African Prostate Study (SAPCS) was initiated in 2008. Recruiting over 2,500 men, we have shown that southern African men are 2.1 times more likely to present with high-risk PCa than African Americans, while within the region, this risk is 1.6 times greater for men living in rural over urban localities. Using state-of-the-art molecular-genetic interrogation, the SAPCS team have reported that high-risk prostate tumors from southern African men have a fourfold greater mutational burden, suggesting a possible environmental mutagenic contributing, at least in part, to adverse disease presentation in Africa. As such, we hypothesize that high-risk PCa associated with African ancestry is a result of a combination of both internal (genetic) and external (non-genetic) forces. Furthermore, we propose that Africa (specifically southern Africa) holds untapped potential to identify missing genetic and non-genetic contributions to African-linked disparity and that a synergistic approach is required to identify these contributions. The objective of TARGET Africa is to interrogate the genome (genome and epigenome) and exposome (the totality of non-genetic exposures of an individual in a lifetime) to uncover the etiology of high-risk PCa and associated disparities in men of African ancestry, with a globally unique focus on rural Africa. In Aim 1, we will perform extensive interrogation of demographic, lifestyle, and behavioral data collected over a decade for 2,500 SAPCS men, 1,500 with and 1,000 without PCa and over half representing rural communities, with the goal to identify modifiable PCa risk factors. Through comparing the 1,500 southern African cases with extensive data collected for 1,000 African Americans from the North Carolina-Louisiana Prostate Cancer Study (PCaP), we will identify African-specific high-risk disease associations irrespective of geography. In Aim 2, we will perform a focused study of 80 SAPCS men from a malaria endemic subsistence farming community exposed annually to DDT residential spraying and 40 SAPCS men from a malaria non-exposed urbanized setting presenting with high-risk PCa and capturing (1) extensive demographic, lifestyle, and behavioral data, (2) environmental pollutant and biochemical exposure and response data; and (3) molecular-genetic data, including whole genome and epigenome, with the goal to identify the accumulative impact of factors, while identifying biomarkers of high-risk PCa. In Aim 3, we will use the power of interrogating whole genome sequenced data for signatures of inherited risk (germline) and carcinogenic exposure (somatic) contributing to high-risk PCa in men of African ancestry by direct comparison of the mutational landscapes from non-African globa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110691
Entities
People
- Vanessa Hayes
Organizations
- Garvan Institute of Medical Research
- United States Army