Sunday, December 22, 2024
12/22/2024
Genomic bases for African geo-ethnic prostate cancer health disparity PROJECT SUMMARY/ABSTRACT With no known cause or modifiable risk factor, prostate cancer (PCa) is characterized by significant geo-ethnic disparity. Men of African ancestry and/or from Africa are at greatest risk for aggressive disease. Compared to non-Africans, African American men are at 2.5 to 5-fold increased risk for lethality. Here we will address if this geo-ethnic disparity is driven by ethnicity (genetics), geography (environment), or a combination. 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, PCa whole genome data is lacking across the African diaspora. While much work in ethnic associated PCa health disparity has addressed the contribution of factors from common germline variants to socioeconomics, these studies have almost exclusively been limited to the United States and remain under debate. Globally, lethal PCa is exasperated in African ancestral regions, including Sub- Saharan Africa and South America with rates 2.5 and 1.6-fold greater than the United States, respectively. Our working hypothesis is that global inclusion provides a unique opportunity to correlate for ethnic and geographic similarities and differences, with men of African ancestry presenting with the greatest genetic diversity, while also representing regions of significant environmental diversity. While the benefits of diversity and inclusion for enhancing genomic medicine are well understood, the benefits to bolster scientific knowledge has been less appreciated. In 2022, this team generated the first African ancestral PCa whole genome data, providing insights ranging from novel African-specific cancer drivers, identifying a larger spectrum of somatic mutational signatures, while describing a clinically relevant African-specific molecular taxonomy. Our study provided the first tantalizing evidence for both ethnic and geographic contributions to African ancestral PCa health disparities. Here we will expand this preliminary work to include African ancestral populations from the US (Chicago), Brazil and South Africa. Through whole genome profiling of 700 men and their tumors, we will identify African-relevant inherited pathogenic variants and cancer drivers, including germline-somatic interactions; identify non-genetic signatures within the complex tumor genome through somatic variant pattern recognition with associated geography over ethnicity, including our newly described Global Mutational Subtyping; while we will harness the power of shotgun genomic interrogation to provide novel insights into the potential role of infectious pathogens. Ultimately, identifying the underlying causes of PCa health disparities has significant implications for advancing our understanding of the etiology, early detection, prevention, and treatment of lethal PCa for all men.
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