ANO7 African-ancestral genomic diversity and advanced prostate cancer

Abstract 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 variant (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 cooccurrence with the recently reported African-specific deleterious risk variant p.Ser914* (rs60985508). Additional findings include, a novel protein truncating African-specific frameshift variant p.Asp789Leu, African-relevant PDVs associated with altered protein structure at Ca 2+ -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.