Professor Vanessa Hayes and her team’s landmark Nature Communications study used whole genome sequencing of African prostate cancer patients to uncover unique genetic variants, paving the way for ancestry-inclusive precision medicine and equitable cancer care.
In a landmark study published in Nature Communications, Professor Vanessa Hayes and her international team have revealed critical genetic insights into prostate cancer (PCa) among African men, a population disproportionately affected by the disease but historically underrepresented in genomic research.
Study cohort
The study, which involved whole genome sequencing (WGS) data of 217 African ancestral PCa patients, highlights the urgent need for ancestry-inclusive germline testing and identifies novel candidate genes that could transform precision medicine for African men.
The research was powered by the Southern African Prostate Cancer Study (SAPCS) and the Pan Prostate Cancer Group (PPCG), with sequencing conducted at the Ramaciotti Centre for Genomics, UNSW Sydney. The Ramaciotti Centre generated high-coverage WGS data (average 43.3X) for 70 previously unpublished SAPCS cases, adding to the 116 published genomes and 31 African ancestral PPCG cases. This comprehensive dataset enabled an untargeted, genome-wide interrogation of small variants, single nucleotide variants (SNVs) and indels, using best-practice pipelines.
African-specific variants
The study identified 172 potentially pathogenic variants across 78 genes related to DNA damage response (DDR) or PCa. Notably, the prevalence of known pathogenic variants in African patients was significantly lower than in non-African populations. This disparity underscores the limitations of current germline testing panels, which are predominantly based on European data.
Among the most impactful genes were BRCA2, ATM, and FANCA- all well-established in PCa germline testing. However, the study also revealed a suite of previously unrecognized candidates with strong pathogenic potential. Findings in this landmark study suggest that African-specific variants may play a critical role in the high mortality rates observed in African PCa patients.
Clinical relevance
To refine candidate selection, the team developed a nine-step ranking system incorporating variant frequency, predicted loss-of-function, clinical presentation, and tumour-matched somatic data. This approach revealed that many African patients with high-ranking variants also presented with advanced disease and elevated prostate-specific antigen (PSA) levels, which further supports the clinical relevance of these findings.
Importantly, the study found that 50% of patients with DNA polymerase variants had tumour mutational burdens above the cohort median, and several showed enrichments for DDR-like mutational signatures. These biological correlations reinforce the potential of these variants to inform treatment strategies, including the use of PARP inhibitors and immunotherapies.
Professor Hayes emphasized the broader implications of the study: “Our findings provide a much-needed framework for African-inclusive germline testing and precision oncology. The current one-size-fits-all approach fails African populations, who are genetically the most diverse and disproportionately affected by PCa mortality.”
Future
The study calls for the development of tailored germline testing panels that reflect the unique genetic landscape of African populations. It also advocates for the use of WGS as a cost-effective alternative to targeted panels, which often miss actionable variants in underrepresented groups.
By leveraging the capabilities of the Ramaciotti Centre for Genomics and integrating data from diverse African cohorts, this research marks an important step toward equitable cancer care. It not only expands the catalogue of PCa-relevant genes but also sets the stage for future clinical trials and functional validation studies across Africa and globally.
