ANO7 African-ancestral genomic diversity and advanced prostate cancer

Prostate Cancer Prostatic Dis. 2024 Sep;27(3):558-565. doi: 10.1038/s41391-023-00722-x. Epub 2023 Sep 25.

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 (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.

MeSH terms

  • Africa, Southern / epidemiology
  • Aged
  • Anoctamins* / genetics
  • Biomarkers, Tumor / genetics
  • Black People* / genetics
  • Case-Control Studies
  • Genetic Predisposition to Disease*
  • Genomics / methods
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / pathology

Substances

  • Anoctamins
  • ANO7 protein, human
  • Biomarkers, Tumor