Early detection is currently the best way to encounter PCa given than no definite treatment exists for the metastatic form of the disease 9. Therefore, identifying risk factors for PCa and the advanced form of the disease in the region is an important step to decrease its burden on the health care system. The incidence of PCa in South Africa has tripled in the last 15 years, which has been contributed to improvements in diagnosis 16. However, little is known about the tumor characteristics and the possible factors for this high incidence. This study was the first of its kind in assessing risk factors of PCa and its aggressiveness among the ancestries of southern Africa in a population-based scale.
It’s previously shown that Black people are more likely than other ethnicities to be diagnosed with PCa in southern Africa 17,18. However, identifying as a Black South African represents a rich ethno-linguistic and as such genetic and cultural diversity 19,20, calling for caution in singularizing African ancestry within the region. This was highlighted in a 2017 study that showed the occurrence of malignancies to vary across different east African population identifiers 21. Through self-reported ethno-linguistic identification, we could further clarify the observed within African risk association and showed that Nguni people were statistically significantly more likely than Europeans to be diagnosed with PCa. Appreciating that this was probably due to the limited number of cases, after adjusting the model for study variables, we found Tsonga and Venda ethnicities were also associated with PCa. With a smaller study population, we have previously shown that Venda Nation to be associated with PCa risk 9. Similar to our study, others have associated gynaecomastia and erectile dysfunction with PCa, which can be due to increased age or PCa treatment 22, however, all SAPCS study participants were treatment naïve at time of recruitment. The association of erectile dysfunction with PCa was no longer observed after adjusting for other variables such as age, suggesting that the older age of the cases was likely driving the positive correlation. One must caution that the controls in this study cannot be regarded as “healthy control” as most of them were elderly men with urological symptoms such as enlarged prostate or cystitis. STDs were also associated with PCa which is in accordance with previous studies 23.
While Nguni, and in particular the Tsonga and Venda population identifiers may predispose South African men to PCa risk, after adjusting for age, we found Tsonga people were more likely to present with advanced form of the disease. To the best of our knowledge this was not investigated previously in a population scale. A possible explanation might be the frequent use of the medicinal plant “Xidomeja” (J. Zeyheri) by the Tsonga, which has been reported to contain diterpenoid which is used in synthetic vitamin E 24. Notably, men using these supplements tend to be diagnosed with high-grade PCa 25,26. Alternatively, this disparity may largely be driven by genetic contributions. Previously we have alluded to a differential ancestral Bantu fraction within the Tsonga versus Sotho-Tswana, while more closely reflecting the Venda peoples 6.
Supporting a previous report that Black South Africans are more likely to be diagnosed with advanced PCa 18, including compared with African Americans 6, we concur with earlier age PSA screening (around 45 years) for men of African ancestry 27, including southern Africans. Adjustment for other variables such as poverty rate could only moderate these associations. Other than the genetic factors, an explanation for this association is that reportedly, only 9.9% of Black South Africans have private health insurance, and are therefore reliant on often over-crowded and under-resourced public healthcare services; while 72.9% of Europeans, 52% of Indians and 17.1% of South African Coloured report having private health insurance 28. Additionally, a recent study in South Africa of 341 PCa cases reported that only 76 (22.3%) had awareness of PCa before diagnosis and less than 50% of the cases sought medical help after being diagnosed 29, and as such we call for further programs focused on bringing education and awareness across the region.
Additionally, we associate a high poverty rate with advanced disease. It is well-established that people with a lower income are less likely to use medical services 30. Red meat consumption can be an indicative of better economic status and was inversely associated with the advanced disease. While in most African cultures red meat was consumed as part of ceremonial celebrations or coming together of families and communities, which contrasts with western cultures, specifically within South Africa where red meat is consumed daily 31. Complete balding patterns was also inversely associated with advanced PCa, which is arguably converse to the inconsistent European-biased studies 32 While some testosterone inhibitors such as finasteride are used for curing baldness in men which also tend to lower PCa and its mortality rate 33, this is unlikely to be commonly used within a less affluent study cohort. Age is usually the predictor of advanced-stage cancer where there is a national screening program for a specific age group 34,35, hence associations between age and the advanced disease was not expected in this study.
Unlike many malignancies, PCa is usually a slow-progressing disease and as such it can be obscure for a long time before its diagnosis 36. Black South Africans were diagnosed at an older age in this study. This again might reflect the poor health seeking attitude, reliance on traditional methods of health care, lack of screening and insurance coverage which causes a delay in PCa diagnosis in this population. However, this delay in diagnosis did not seem to be the cause of the advanced disease among Africans since the associations were still significant after adjusting for age. People with a positive family history of PCa being diagnosed at a younger age showed that there was probably a wariness in this population about PCa. In addition, PCa with a pathogenic genetic variant usually occurs at a younger age 37. Some of the factors associated with an old-age diagnosis of PCa such as residing in subsistence farming areas are likely to reflect poor socioeconomic status. Since it is well-established that Black ethnicity is a risk factor for PCa2, the observations that Black South Africans are less likely to have a PCa family history, is suggestive that many Black South Africans remain undiagnosed. The same applies for diabetes since the disease is known to be more common among people with an African ancestry 38, but our results showed that Africans are less likely to have diabetes.
The interaction term analysis was used to determine whether any of the study variables have different associations with advanced disease in Black southern Africans compared with non-African ethnicities. Red meat consumption was significantly a stronger predictor of advanced PCa in Black South Africans compared with others. This may stem from the fact that men of European ancestry are more likely to voluntarily choose vegetarianism, while red meat consumption better reflects the economic status for Black South Africans 39,40. STDs also put Black men at greater risk for presenting with ISUP > 3 disease. In other words, a Black South African man is significantly more likely to be diagnosed with ISUP > 3 if he has STD than a non-Black man with STD. This shows that in addition to screening for PCa, awareness should be raised among the Black community to preserve their sexual health. Age of older than 75 was also a less decisive factor for being diagnosed with the advanced disease for African men, with ISUP group grades more akin to people younger than 60 years if they were from the Black South Africans.
The main strength of this study was the broad coverage of PCa cases over two provinces of South Africa and investigating some novel factors in the most genetically diverse population of the world which can lead to discover the reason for high incidence and mortality of PCa in this population. Limitations included a high number of missing information, which highlights the challenges faced when working within under-resourced communities. As such, the inclusion of the sensitivity analysis for unknown cases provided some reassuring known PCa significances, for example Aspirin use reducing PCa risk 41 and presence of STDs increasing risk 42. While arguably under-powered compared to European-biased epidemiological studies, as the world recognises the importance for inclusivity and equity, specifically with regards to under-representation across the African diaspora, this study provides important insights as the largest regionally defined Sub-Saharan PCa study of its kind to date.