Data-mining approach for screening of rare genetic elements associated with predisposition of prostate cancer in South-Asian populations

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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ANO7 African-ancestral genomic diversity and advanced prostate cancer

Hayes

Jiang

Soh

et al. 2023

Preprint

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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 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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Data-mining approach for screening of rare genetic elements associated with predisposition of prostate cancer in South-Asian populations

Cited by 3 publications

References 31 publications

Identification of the potential type 2 diabetes susceptibility genetic elements in South Asian populations

Identification of the potential type 2 diabetes susceptibility genetic elements in South Asian populations

ANO7 African-ancestral genomic diversity and advanced prostate cancer

ANO7 African-ancestral genomic diversity and advanced prostate cancer

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