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<p>African men are disproportionately impacted by aggressive prostate cancer (PCa). The key to this disparity is both genetic and environmental factors, alluding to epigenetic modifications. However, African-inclusive prostate tumour DNA methylation studies are lacking. Assembling a multi-geo-ancestral prostate tissue cohort, including men with (57 African, 48 European, 23 Asian) or without (65 African) PCa, we interrogate for genome-wide differential methylation. Overall, methylation appears to be driven by ancestry over geography (152 southern Africa, 41 Australia). African tumours show substantial heterogeneity, with universal hypermethylation indicating more pervasive epigenetic silencing, encompassing PCa suppressor genes and enhancer-targeted binding motifs. Conversely, African tumour-associated heterochromatic hypomethylation suggests chromatin relaxation and developmental pathway activation via enhancer targets. Notably, non-prostate lineage elements appeared preferentially exploited in African tumorigenesis, with ancestry potentially influencing the extent of lineage-inappropriate activation, and tumour progression marked by repression of developmental regulators. Together, these findings point to extensive epigenetic plasticity in African tumours, with intergenic regulatory remodelling promoting genomic instability, metastatic potential and aggressive disease phenotypes.</p>

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Methylation reprogramming associated with aggressive prostate cancer and ancestral disparities

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月7日

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  • Jenna Craddock,
  • Pavlo Lutsik,
  • Pamela X Y Soh,
  • Melanie Louw,
  • Md Mehedi Hasan,
  • Sean M Patrick,
  • Shingai B A Mutambirwa,
  • Phillip D Stricker,
  • Hagen E A Förtsch,
  • Gail S Prins,
  • Peter Mungai Ngugi,
  • Weerachai Jaratlerdsiri,
  • Winstar Mokua Ombuki,
  • Daniel M Moreira,
  • Ikenna C Madueke,
  • Maphuti Tebogo Lebelo,
  • Tumisang M N Mbeki,
  • Muvhulawa Obida,
  • Martin Obida,
  • Raymond A Campbell,
  • Mulalo B Radzuma,
  • Golda Stellmacher,
  • Jessie Gamxamub,
  • Reginald M J Menoe,
  • Jue Jiang,
  • Tingting Gong,
  • Korawich Uthayopas,
  • Kazzem Gheybi,
  • Ruotian Huang,
  • Kangping Zhou,
  • Umuna Maendo,
  • Massimo Loda,
  • Giuseppe Nicolo’ Fanelli,
  • David C Wedge,
  • Avraam Tapinos,
  • Vivien Holmes,
  • Robert G Bristow,
  • Daniel S Brewer,
  • Abraham Gihawi,
  • Colin S Cooper,
  • Rosalind A Eeles,
  • Zsofia Kote-Jarai,
  • Maria Argos,
  • Irene Barnhoorn,
  • Lynn Birch,
  • Muriuki Elias Nyaga,
  • Micah O Oyaro,
  • Joyce Shirinde,
  • Douglas I Walker,
  • Edwin O O Walong,
  • Githui Shila Wanjiku,
  • Margaret Quaid,
  • M S Riana Bornman,
  • Clarissa Gerhäuser,
  • Vanessa M Hayes

摘要

African men are disproportionately impacted by aggressive prostate cancer (PCa). The key to this disparity is both genetic and environmental factors, alluding to epigenetic modifications. However, African-inclusive prostate tumour DNA methylation studies are lacking. Assembling a multi-geo-ancestral prostate tissue cohort, including men with (57 African, 48 European, 23 Asian) or without (65 African) PCa, we interrogate for genome-wide differential methylation. Overall, methylation appears to be driven by ancestry over geography (152 southern Africa, 41 Australia). African tumours show substantial heterogeneity, with universal hypermethylation indicating more pervasive epigenetic silencing, encompassing PCa suppressor genes and enhancer-targeted binding motifs. Conversely, African tumour-associated heterochromatic hypomethylation suggests chromatin relaxation and developmental pathway activation via enhancer targets. Notably, non-prostate lineage elements appeared preferentially exploited in African tumorigenesis, with ancestry potentially influencing the extent of lineage-inappropriate activation, and tumour progression marked by repression of developmental regulators. Together, these findings point to extensive epigenetic plasticity in African tumours, with intergenic regulatory remodelling promoting genomic instability, metastatic potential and aggressive disease phenotypes.