Jiang, JueSoh, Pamela X.Y.Mutambirwa, Shingai B.A.Bornman, Maria S. (Riana)Haiman, Christopher A.Hayes, Vanessa M.Jaratlerdsiri, Weerachai2024-09-192024-09-192024-09Jiang, J., Soh, P.X.Y., Mutambirwa, S.B.A. et al. ANO7 African-ancestral genomic diversity and advanced prostate cancer. Prostate Cancer and Prostatic Diseases 27, 558–565 (2024). https://doi.org/10.1038/s41391-023-00722-x.1365-7852 (print)1476-5608 (online)10.1038/s41391-023-00722-xhttp://hdl.handle.net/2263/98320DATA AVAILABILITY : The data used in this study will be made available on request.BACKGROUND : Prostate cancer (PCa) is a significant health burden for African men, with mortality rates more than double global averages. The prostate specific Anoctamin 7 (ANO7) gene linked with poor patient outcomes has recently been identified as the target for an African-specific protein-truncating PCa-risk allele. METHODS : Here we determined the role of ANO7 in a study of 889 men from southern Africa, leveraging exomic genotyping array PCa case-control data (n = 780, 17 ANO7 alleles) and deep sequenced whole genome data for germline and tumour ANO7 interrogation (n = 109), while providing clinicopathologically matched European-derived sequence data comparative analyses (n = 57). Associated predicted deleterious variants (PDVs) were further assessed for impact using computational protein structure analysis. RESULTS : Notably rare in European patients, we found the common African PDV p.Ile740Leu (rs74804606) to be associated with PCa risk in our case-control analysis (Wilcoxon rank-sum test, false discovery rate/FDR = 0.03), while sequencing revealed co-occurrence with the recently reported African-specific deleterious risk variant p.Ser914* (rs60985508). Additional findings included a novel protein-truncating African-specific frameshift variant p.Asp789Leu, African-relevant PDVs associated with altered protein structure at Ca2+ binding sites, early-onset PCa associated with PDVs and germline structural variants in Africans (Linear regression models, −6.42 years, 95% CI = −10.68 to −2.16, P-value = 0.003) and ANO7 as an inter-chromosomal PCa-related gene fusion partner in African derived tumours. CONCLUSIONS : Here we provide not only validation for ANO7 as an African-relevant protein-altering PCa-risk locus, but additional evidence for a role of inherited and acquired ANO7 variance in the observed phenotypic heterogeneity and African-ancestral health disparity.en© Crown 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License.Prostate cancerCancer geneticsPredictive markersSDG-03: Good health and well-beingArticle