Prostate cancer risk in men of differing genetic ancestry and approaches to disease screening and management in these groups

Abstract

Prostate cancer is the second most common solid tumour in men worldwide and it is also the most common cancer affecting men of African descent. Prostate cancer incidence and mortality vary across regions and populations. Some of this is explained by a large heritable component of this disease. It has been established that men of African and African Caribbean ethnicity are predisposed to prostate cancer (PrCa) that can have an earlier onset and a more aggressive course, thereby leading to poorer outcomes for patients in this group. Literature searches were carried out using the PubMed, EMBASE and Cochrane Library databases to identify studies associated with PrCa risk and its association with ancestry, screening and management of PrCa. In order to be included, studies were required to be published in English in full-text form. An attractive approach is to identify high-risk groups and develop a targeted screening programme for them as the benefits of population-wide screening in PrCa using prostate-specific antigen (PSA) testing in general population screening have shown evidence of benefit; however, the harms are considered to weigh heavier because screening using PSA testing can lead to over-diagnosis and over-treatment. The aim of targeted screening of higher-risk groups identified by genetic risk stratification is to reduce over-diagnosis and treat those who are most likely to benefit.

Fig. 1. World map showing age standardised world incidence rate of prostate cancer.

Map showing estimated age-standardised incidence rates for PrCa worldwide in 2018, in males including all ages [1].

Fig. 2. World map showing age standardised world mortality rate of prostate cancer.

Map showing estimated age-standardised mortality rates for PrCa worldwide in 2018, in males including all ages [1].

Fig. 3. Manhattan plot using the trans-ancestry GWAS January 2021 [65].

The chromosomes are numbered 1–23 in alternating black and grey. The blue dotted line represents genome-wide significance p < 5 × 10⁻⁸. The green dots represent the 269 known PrCa susceptibility loci hits in the multi-ethnicity group. The red dots represent the hits reaching a significant level for AFR but not for EUR. Six regions have specific signals for the AFR population.

Fig. 4. Boxplot depicting risk allele frequency (RAF) of PrCa susceptibility variation in men of African ancestry (AFR) in peach and men of European ancestry (EUR) in cyan.

Panel a shows the overall RAF in AFR men and EUR men for all 269 variants. Panel b Depicts RAFs in both populations stratified by grouped odds ratios from 1 to 1.5, demonstrating that mean RAF of PrCa susceptibility loci is elevated in AFR men for variants with higher effect sizes. c An expanded view of RAF for variants with an odds ratio greater than 1.5 showing that these moderate penetrance risk alleles occur more frequently in men of African ancestry.

Fig. 5. Barchart depicting rate of over-diagnosis of prostate cancer and polygenic risk score in quartiles.

Bar chart with rate of over-diagnosis of PrCa by polygenic risk quartile showing the proportion of prostate cancers likely to be over-diagnosed varies inversely with polygenic risk [68].