Abstract B111: Population genetics identifies distinct subsets of prostate cancer risk variants between men of European, African and East Asian ancestry

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Abstract Introduction Genome-wide association studies (GWAS) have identified Single Nucleotide Polymorphisms (SNPs) or variants associated with prostate cancer risk. The contribution of human genetic variation to racial disparities in prostate cancer is still not clearly understood. Men of African ancestry have the highest risk of prostate cancer, followed by European ancestry and lowest in men with East Asian ancestry. Prostate cancer is the most common cancer in human males, but non-human large primates do not develop prostate cancer naturally. This study investigated the population genetics of prostate cancer SNPs to identify those that were unique to ancestral groups, and also comparative genomics of human risk alleles and orthologous alleles in primates. Methods Prostate cancer SNPs were obtained from previous GWAS studies in the GWAS Catalog (https://www.ebi.ac.uk/gwas/home), and the GWAS Diversity Monitor Database (https://gwasdiversitymonitor.com). SNPs identified from discovery stages in AFR and EAS populations were included even when they did not replicate in EUR populations. Using Ensemble Release 109 (https://www.ensembl.org), the risk allele frequencies (RAF) in European (EUR), African (AFR) and East Asian (EAS) populations were obtained from the 1000 Genomes project and other population genetics data available on Ensembl. Population RAFs were used to identify variants that were present in only one ancestral group and not shared by other ancestral groups. A SNP was considered unique to a population if it was present in >1% of that population, but present in <.01% of the others. The risk alleles in Homo sapiens were compared to the orthologous ancestral primate allele using genome alignments from 10 primate species. Results 520 prostate cancer-associated SNPs were identified. 484 were shared between EUR, AFR and EAS populations. 10 SNPs were unique to EUR (on chromosomes 1, 2, 5, 8, 11, 17, 21, 22), 19 to AFR (on chromosomes 1, 5, 6, 8, 13, 17, 22) and 7 to EAS (on chromosomes 2, 10, 12, 13) populations. The gene sets involved by these SNPs were different in each ancestral group, with some overlap between EUR and AFR genes sets, but no overlap with the EAS genes set. The risk allele for all the 36 SNPs that were unique to EUR, AFR or EAS populations was different from the ancestral primate allele. Conclusion Prostate cancer SNPs unique to EUR, AFR and EAS populations were identified and are likely to be driving the genetic component of prostate cancer racial disparities. The genes involved were different between populations, which could have biological consequences and lead to distinct cancer phenotypes in men from different ancestral groups. The unique SNPs all had alleles different from the ancestral primate allele, suggesting that these variants emerged after human speciation and ‘Out of Africa’ human migration events. Citation Format: Chidi N. Molokwu, Evi O. Useh, Suresh Venugopal. Population genetics identifies distinct subsets of prostate cancer risk variants between men of European, African and East Asian ancestry [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B111.