INTRODUCTION
Despite economically stable transitioned countries recording the highest prostate cancer incidence rates, in contrast mortality rates are disproportionately elevated in global regions of economic transition, with a bias towards Sub-Saharan Africa [1]. However, controlling for economic status and healthcare access, the United States Veterans Health Administration Cohort comparing 75-thousand Black and 207-thousand White male veterans, found Black men to have double the prostate cancer risk at a younger age, with more aggressive disease presentation [2]. A highly heritable cancer, African ancestry is a significant risk factor, while disease presentation is both biologically and genomically unique [3]. Ranked the lead cause of male associated cancer deaths in Sub-Saharan Africa [4], with rates almost 3-fold greater than the United States, while surpassing the Caribbean in Southern and Central Africa [1], we and others have called for the inclusion of African nations in prostate cancer health disparity studies.
UNITED STATES DEPARTMENT OF DEFENSE RECOGNITION FOR PROSTATE CANCER HEALTH EQUITY RESEARCH AND OUTCOMES IMPROVEMENT
Recognising the lack of global health efforts, the United States Department of Defense (DoD) and Prostate Cancer Research Program initiated the FY21 Health Equity Research and Outcomes Improvement Consortium (HEROIC) Award, funding 2 teams. The Inclusive Cancer Care Research Equity (iCCaRE) for Black Men Consortium, led out of the Mayo Clinic Community Health Initiative in Florida, is focused on providing quality care, support, skills and solutions tailored for Black men diagnosed with prostate cancer in the United States and West Africa. The HEROIC Prostate Cancer Precision Health (PCaPH) Africa1K Consortium, led out of the University of Sydney in Australia, with partner leads at the University of Pretoria in South Africa, the University of Nairobi in Kenya and the University of Illinois at Chicago in the United States, is using a single model design to establish a representative Southern, East, West African and African American inclusive resource (1,000 Black men) to interrogate patient-matched genomic, lifestyle and environmental data aimed at establishing African-relevant criteria for prostate cancer treatment and prevention.
LESSONS FROM FIRST PROSTATE CANCER WHOLE-GENOME DATA GENERATED FOR SUB-SAHARAN AFRICA, THE SOUTHERN AFRICAN PROSTATE CANCER STUDY
As the first of the developed study sites, the Southern African Prostate Cancer Study (SAPCS) is providing the HEROIC PCaPH Africa1K members with foundational, yet currently unmet, data for the continent. Notably, we report a 2.1-fold and 4.8-fold increase in National Comprehensive Cancer Network criterion for histopathological and prostatespecific antigen defined high-risk disease in Black South African versus Black American men, respectively [5]. Generating germline and somatic data, genomic disparities between Black South African and Black American and non-African men include from rare pathogenic and common risk variants [6,7], to a greater contribution of Africanspecific cancer drivers and therapeutic targets [8-10]. Furthermore, the identification of a new computationally derived molecular taxonomy (global mutational subtypes, GMSs), provides tantalising evidence for a regionally specific environmental carcinogen [8]. While scarce, data is emerging that genomic-based disparities extend across Sub-Saharan Africa [7,11,12]. Country and regional differences include ancestrally driven cancer-type specific risk in Kenya [13], and exasperated prostate cancer disease in rural over urban Black South Africans [5].
DISPARITIES ACROSS THE SOUTHERN AFRICAN RURAL-URBAN DIVIDE
We urge for caution in viewing ‘Africa’ and African’ in singular terms. The rich cultural and genetic diversity of Sub-Saharan Africa, as evidenced by over 2,000 languages, is in rapid urbanisation-driven societal transition. With 57% of Sub-Saharan Africa living rurally, the HEROIC PCaPH Africa1K have embraced an inclusive recruitment model, representing South Africa’s most extensive rural (Limpopo) and urban (Gauteng) Provinces (Fig. 1A). Reliant on largely subsistence farming, rural communities experience lower economic status, with links to aggressive prostate cancer [14], while upholding traditional values. Recruiting in the rural capital (Polokwane) and a traditional village-based setting (Vhembe), 89.5% of Vhembe participants report ‘rite of passage to manhood’ circumcision, almost double that of urban sites (Table 1). While community-based surveys suggest less than a quarter of Vhembe men elect traditional-over western-based healthcare, the impact on loss of wages due to vast distances to clinics, unrealistic wait times and over-crowding, is escalating alternative health seeking behaviour. Concurring with others [15], we observe low prostate cancer awareness, although the overall sense from the community, local leaders, healthcare workers and traditional healers is more needs to be done for men’s health. Within the rural SAPCS communities, men are ‘calling for a voice.’ Establishing the first urology clinic in the region, including local training, over 120 diagnostic biopsies were performed in the first year.
In contrast, SAPCS urology clinics are well established in the urban metropolis. Although recruits present earlier (average 6 years), the rapid pace of urbanisation presents the team with a different set of challenges. Significantly more likely to represent both inter-continental and non-African genetic admixture (Fig. 1B), in contrast, rural participants show the benefits of parental and even 2nd-generational shared ethnicity (Table 1). Furthermore, rural men are significantly more likely to have been born (Fig. 1C) and lived a lifetime (Fig. 1D) in the same regional location, and in turn less likely to be impacted by varied lifestyle influences and environmental exposures. Conversely, cross-border, urban-urban and rural-urban migration has a major impact on urban community variability with potential to lead to spurious results.
This rural-urban disparity is further highlighted through tumour genome profiling. While urban recruits presented with a greater proportion of rarer African-specific subtypes (GMS-B and -D), rural patients were significantly more likely to present with GMS-C (Fig. 1E), previously linked to poor prognosis [8]. Including a notable (yet under-powered) contribution from Vhembe (4 of 5 participants, Table 1), one may speculate on a plausible contributing environmental carcinogen. Uniquely, the Vhembe community are annually exposed to the endocrine disrupting chemical dichlorodiphenyltrichloroethane through indoor spraying for malaria control, linked further to altered hormone levels in adult males [16]. Ultimately, inclusion is crucial for understanding the environmental determinants on prostate cancer risk in these vulnerable populations.
CONCLUSION
We argue that including rural Sub-Saharan African communities in prostate cancer health disparity studies is crucial for controlling cultural (nongenetic) and ancestral (genetic) confounders, establishing population-relevant model for precision medicine, while drilling into the potential contribution of environmental exposures. This approach could unveil novel insights into prostate cancer aetiology, promote global health equity, while lead to targeted interventions in underserved populations that goes beyond the benefits of genomics alone.
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