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ANO7 African-ancestral genomic diversity and advanced prostate cancer
Jiang, J. Soh, P. X. Y. Mutambirwa, S. B. A. Bornman, M. S. R. Haiman, C. A. Hayes, Vanessa M Jaratlerdsiri, W.
Jiang, J.
Soh, P. X. Y.
Mutambirwa, S. B. A.
Bornman, M. S. R.
Haiman, C. A.
Hayes, Vanessa M
Jaratlerdsiri, W.
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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.
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Date
2023
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Jiang J, Soh PXY, Mutambirwa SBA, Bornman MSR, Haiman CA, Hayes VM, et al. ANO7 African-ancestral genomic diversity and advanced prostate cancer. Prostate Cancer Prostatic Dis. 2023 Sep 25. PubMed PMID: 37749167. Epub 2023/09/26. eng.