Abstract 2402: Comparative genomics at prostate cancer risk loci to identify human-specific risk variants predisposing the human male to prostate cancer

Abstract Introduction: Prostate cancer (PCa) is the most common cancer in the human male but is absent in other primates, including our closest extant relative the chimpanzee. Predisposition to PCa is multifactorial and includes both genetic and environmental factors. Genome wide association studies (GWAS) have identified hundreds of PCa associated single nucleotide polymorphisms (SNPs), but it is not clear which SNPs are the most relevant to carcinogenesis and disease progression. PhyloP scores are a measure of conservation between species at each position in the aligned genome, with positive scores indicating higher conservation. Human Accelerated Regions (HARs) are regions in the genome that show conservation between mammalian species but unexpected divergence in humans. A comparative genomics approach was used to identify SNPs and candidate genes that confer PCa risk on the human male. Methods: PCa associated SNPs were obtained from studies submitted to the GWAS Catalog (https://www.ebi.ac.uk/gwas/home), and the GWAS Diversity Monitor Database (https://gwasdiversitymonitor.com). Risk Allele Frequencies (RAFs) were obtained from Ensembl (https://www.ensembl.org/), using regional classifications and RAF data from the 1000 Genomes. Human and chimpanzee genomes were aligned using the Cactus genome alignment tool (https://cglgenomics.ucsc.edu/data/cactus/). PhyloP scores were determined for each SNP position and the closest HAR was identified using the Bedtools package. The allele for each specie at the PCa SNP position was compared to determine positions where the PCa risk allele was divergent from the ancestral primate allele. Results: 520 PCa associated SNPs were identified. Eleven SNPs occurred at positions with PhyloP score>1.0, and where the PCa risk allele was different from the chimpanzee allele. Two of the 11 SNPs had the risk allele occurring in more than half of humans (rs6062509 at 71%, and rs8064454 at 58%). Two SNPs with the highest PhyloP scores had RAFs of 11% for rs76832527 (PhyloP score 8.616) and 17% for rs2277283 (PhyloP score 3.842). A non-coding region of chromosome 8 containing rs870167 had RAF of 17% in humans. ZGPAT, HNF1B, ANO7, INCENPS, GATA2-AS1 and CLND23 were identified as candidate genes for prostate cancer carcinogenesis and/or progression. There was no overlap of PCa associated SNPs with HAR regions. Conclusions: Six candidate genes harbored PCa risk SNPs that are in loci that show high conservation between mammalian species, but a divergent PCa risk allele in human males. ZGPAT, HNF1B, ANO7 and GATA2-AS1 are relevant to PCa progression and are candidate genes for human-specific predisposition to PCa. Further studies on these genes and non-coding loci are needed to determine their role in PCa predisposition in the human male. Citation Format: Chidi N. Molokwu. Comparative genomics at prostate cancer risk loci to identify human-specific risk variants predisposing the human male to prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2402.