Abstract 774: Genetic architecture, evolutionary genomics, and genomic risk of prostate cancer in sub-Saharan Africa

Abstract Men of African descent have the highest prostate cancer (CaP) incidence and mortality rates, yet the genetic basis of CaP in African men has been understudied. We performed the first large-scale genomic analysis of CaP across sub-Saharan Africa (SSA). We evaluated the evolutionary history of CaP-associated loci, generated a novel genomic risk score, inferred ancestry-specific genetic architectures, and fine-mapped disease associations using in 3,963 CaP cases and 3,509 controls recruited in Ghana, Nigeria, Senegal, South Africa, and Uganda through the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network. Fifteen independent associations at 8q24.21, 6q22.1, and 11q13.3 reached genome-wide significance, including four novel associations. Multiple lead SNPs were private alleles in SSA, a pattern arising from recent mutations and the out-of-Africa bottleneck. These SSA-specific alleles contribute to haplotypes with odds ratios for CaP above 2.4. The genetic architecture of CaP differs across SSA, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that SSA CaP associations are largely governed by neutral evolution, as opposed to natural selection. This finding is consistent with the late onset of this disease. Focusing on 2,502 age-matched cases and 2,222 non-cancer controls, we generated a novel genomic predictor of CaP. We then assessed the extent to which this polygenic risk score was correlated with age of onset, PSA levels, genetic ancestry, and family history of study participants. The performance of this novel polygenic risk score was tested on other populations of African descent, as well as populations with non-African ancestry. Our findings emphasize the utility of conducting genetic studies in diverse populations. Citation Format: Timothy R. Rebbeck, Rohini Janivara, Wenlong C. Chen, Ujani Hazra, MADCaP Network, Joseph Lachance. Genetic architecture, evolutionary genomics, and genomic risk of prostate cancer in sub-Saharan Africa [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 774.