African-specific molecular taxonomy of prostate cancer

Abstract

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Transcriptomic profiling and genomic rearrangement landscape of Nigerian prostate cancer

“…33,34 While limited in sample size, our study suggests that rare fusion events beyond TMPRSS2-ERG may drive PCa in men of Nigerian ancestry. A recent study by Jaratlerdsiri et al 35 showed that PCa…”

“…While limited in sample size, our study suggests that rare fusion events beyond TMPRSS2‐ERG may drive PCa in men of Nigerian ancestry. A recent study by Jaratlerdsiri et al 35 showed that PCa samples from men of African ancestry have high genomic mutational burden and have more genomic heterogeneity compared to samples from European ancestry. In our study, the detection of rare fusion events in Nigerian PCa may suggest a potentially high level of gene‐rearrangement heterogeneity within Nigerian PCa patients compared to European patients, though we lack representative transcriptomic profiles for Nigerian PCa patients of African ancestry from the African continent.…”

African inclusion in prostate cancer genomic studies provides the first glimpses into addressing health disparities through tailored clinical care

“…On 31 August 2022, we published two papers simultaneously in Nature and Genome Medicine, aimed at providing a first glimpse into the genomic contribution to PCa health disparity for men from Sub‐Saharan Africa. 3 , 4 Generating deep sequenced blood and matched tumour genome data for 183 largely treatment naïve and clinicopathologically aggressive disease‐presenting patients, besides 53 Australians and seven Brazilians, the study included 123 South Africans. Through ancestral interrogation of inherited variation, patients were further genetically classified as African ( n = 113; all South African), European ( n = 61; 53 Australian, five South African, and three Brazilian) or Admixed ( n = 9; five South African and four Brazilian).…”

Simultaneous subset tracing and miRNA profiling of tumor-derived exosomes via dual-surface-protein orthogonal barcoding

“…Prostate cancer (PCa) is one of the most prevalent diagnosed malignancies affecting men worldwide, with increasing cancer-related mortality [43][44][45] . Currently, the widely used serum prostate-specific antigen (PSA) screening lacks sufficient specificity and sensitivity for clinical diagnosis of PCa.…”