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Prostate cancer ancestral genomic disparity

Prostate cancer is characterised by significant global disparity; mortality rates in SubSaharan Africa are double to quadruple those in Eurasia. Hypothesising unknown interplay between genetic and non-genetic factors, tumour genome profiling envisages contributing mutational processes. Through whole-genome sequencing of treatment-naïve prostate cancer from 183 ethnically/globally distinct patients (African versus European), we generate the largest cancer genomics resource for Sub-Saharan Africa. Identifying ~2 million somatic variants, Africans carried the greatest burden. We describe a new molecular taxonomy using all mutational types and ethno39 geographic identifiers, including Asian. Defined as Global Mutational Subtypes (GMS) A–D, although Africans presented within all subtypes, we found GMS-B to be ‘African-specific’ and GMS-D ‘African-predominant’, including Admixed and European Africans. Conversely, Europeans from Australia, Africa and Brazil predominated within ‘mutationally-quiet’ and ethnically/globally ‘universal’ GMS-A, while European Australians shared a higher mutational burden with Africans in GMS45 C. GMS predicts clinical outcomes; reconstructing cancer timelines suggests four evolutionary trajectories with different mutation rates (GMS-A, low 0.968/year versus D, highest 1.315/year). Our data suggest both common genetic factors across extant populations and regional environmental factors contributing to carcinogenesis, analogous to gene-environment interaction defined here as a different effect of an environmental surrounding in persons with different ancestries or vice versa. We anticipate GMS acting as a proxy to intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001009066 HiSeq X Ten Illumina NovaSeq 6000 106
EGAD00001009067 HiSeq X Ten Illumina NovaSeq 6000 260
Publications Citations
African-specific molecular taxonomy of prostate cancer.
Nature 609: 2022 552-559
24
Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers.
Genome Med 14: 2022 100
11
Alterations in the Epigenetic Machinery Associated with Prostate Cancer Health Disparities.
Cancers (Basel) 15: 2023 3462
1
Prostate cancer genetic risk and associated aggressive disease in men of African ancestry.
Nat Commun 14: 2023 8037
5
The impact of telomere length on prostate cancer aggressiveness, genomic instability and health disparities.
Sci Rep 14: 2024 7706
1