Global Molecular Taxonomies Were Generated for Prostate Cancer

Genomic studies of prostate cancer are lacking in individuals from sub-Saharan Africa despite this patient population demonstrating much greater mortality rates. To determine both genetic and nongenetic factors associated with the increased mortality of prostate cancer in individuals of African ancestry, Jaratlerdsiri and colleagues used high-depth whole-genome sequencing and described the largest prostate cancer genomics data involving 123 South African men, as well as 53 Australian and seven Brazilian men to control for study artifacts. Two-million somatic variants were generated and assessed using genetic ancestral classification and revealed a greater number of acquired genetic alterations in African individuals as well as a greater percentage of genome alteration. Evaluation of oncogenic drivers revealed that Africans display a greater number of protein-coding mutations, with FOXA1, PTEN, SPOP, and TP53 being the most commonly mutated driver genes, while copy-number alterations and mutations in SETBP1, DDX11L1, STK19, and NCOA2 were also more likely to occur in African individuals. Moreover, four global mutational subtypes (GMS) were generated, with these taxonomies indicating African individuals were dispersed among all four subtypes, with GMS-B (high copy-number gain) and GMS-D (highest mutational density) being specific to African populations. Conversely, European patients from Australia and Brazil were limited to GMS-A (mutationally silent) and GMS-C (high copy-number loss), while Chinese-Asian individuals were included in GMS-A, suggesting the universal nature of GMS-A. Additionally, these taxonomies were associated with clinical outcome, with the universal (GMS-A) demonstrating better results than the European-African GMS (GMS-C). Mutational timelines for these GMS subtypes were also generated and showed each follows a specific evolutionary pattern, suggesting tumors can differ in the time needed to reach full malignant potential. In summary, this study offers both a global whole-genome resource and molecular taxonomies for prostate cancer that provide evolutionary history and a greater understanding of disease etiology.

Jaratlerdsiri W, Jiang J, Gong T, Patrick SM, Willet C, Chew T, et al. African-specific molecular taxonomy of prostate cancer. Nature 2022;609:552–9.

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