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<p>Prostate cancer (PrCa) incidence and severity vary across ancestries; men of African ancestry (AA) are more likely to be diagnosed and die from PrCa than those of European ancestry (EA). Current polygenic risk scores, even from multi-ancestry GWAS, do not fully capture population-specific genetic mechanisms, especially those mediated by non-coding regulatory single nucleotide polymorphisms (SNPs). Using a deep learning model of prostate enhancers, we identify ~ 2000 SNPs, potentially affecting enhancer function, with higher alternate allele frequency in AA men, that may affect PrCa risk. These SNPs may promote cancer via two mechanisms: increased enhancer activity leading to immune suppression and telomere elongation or decreased activity causing de-differentiation and apoptosis inhibition. Identified SNPs predominantly modulate binding of key transcription factors such as FOX, HOX, and AR – the first was experimentally validated. Incorporating these SNPs into a polygenic risk score improves PrCa risk assessment beyond existing GWAS-identified variants.</p>

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Non-coding genetic variants underlying higher prostate cancer risk in men of African ancestry

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月20日

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  • Shan Li,
  • Kaniz Fatema,
  • Nidharshan Sundarraj,
  • Arashdeep Singh,
  • Padma Sheila Rajagopal,
  • Dimple Notani,
  • David Y. Takeda,
  • Sridhar Hannenhalli

摘要

Prostate cancer (PrCa) incidence and severity vary across ancestries; men of African ancestry (AA) are more likely to be diagnosed and die from PrCa than those of European ancestry (EA). Current polygenic risk scores, even from multi-ancestry GWAS, do not fully capture population-specific genetic mechanisms, especially those mediated by non-coding regulatory single nucleotide polymorphisms (SNPs). Using a deep learning model of prostate enhancers, we identify ~ 2000 SNPs, potentially affecting enhancer function, with higher alternate allele frequency in AA men, that may affect PrCa risk. These SNPs may promote cancer via two mechanisms: increased enhancer activity leading to immune suppression and telomere elongation or decreased activity causing de-differentiation and apoptosis inhibition. Identified SNPs predominantly modulate binding of key transcription factors such as FOX, HOX, and AR – the first was experimentally validated. Incorporating these SNPs into a polygenic risk score improves PrCa risk assessment beyond existing GWAS-identified variants.