Racial disparities in prostate cancer: A complex interplay between socioeconomic inequities and genomics

Abstract

The largest US cancer health disparity exists in prostate cancer, with Black men having more than a two-fold increased risk of dying from prostate cancer compared to all other races. This disparity is a result of a complex network of factors including socioeconomic status (SES), environmental exposures, and genetics/biology. Inequity in the US healthcare system has emerged as a major driver of disparity in prostate cancer outcomes and has raised concerns that the actual incidence rates may be higher than current estimates. However, emerging studies argue that equalizing healthcare access will not fully eliminate racial health disparities and highlight the important role of biology. Significant differences have been observed in prostate cancer biology between ancestral groups that may contribute to prostate cancer health disparities. Notably, relative to White men, Black men with prostate cancer exhibit increased androgen receptor signaling, genomic instability, metabolic dysregulation, and inflammatory and cytokine signaling. Immediate actions are needed to increase multi-center, interdisciplinary research to bridge the gap between social and biological determinants of prostate cancer health disparities.

1. Introduction

In 1854, British surgeon-pathologist Sir Henry Thompson described the first case of prostate carcinoma. Today, over 160 years later, prostate cancer has become the most frequently diagnosed cancer among males in 112 countries around the globe. According to the 2020 GLOBOCAN report, a total of 375,304 men worldwide died from prostate cancer-related deaths, with some of the highest mortality rates being recorded in the Caribbean (27.9 deaths per 100,000) and sub-Saharan African (24.8 deaths per 100,000) regions [1]. Prostate cancer has the largest disparities by race of any cancer. In the United States, between 2012 and 2018, the age-adjusted overall incidence rate of prostate cancer was 171.6 per 100,000 Black men compared to 97.7 per 100,000 non-Hispanic White men (1.76-fold higher in Black men), and 53.8 per 100,000 in Asian/Pacific Islanders (3.19-fold higher in Black men). The age-adjusted overall mortality due to prostate cancer in the US between 2015 and 2019 in Black men was the highest in the world; 38.3 per 100, 000 Black men compared to 17.9 per 100,000 in non-Hispanic White men (2.14-fold higher) and 8.8 per 100,000 in Asian/Pacific Islanders (4.35-fold higher) (Fig. 1) [2,3]. Importantly, age-specific comparisons using Surveillance, Epidemiology, and End Results Program (SEER) data illustrate significant racial differences in prostate cancer incidence during different periods of life (See Table 1 for age-stratified incidence and mortality rates). These notable differences across races in both incidence and mortality rates lead us to hypothesize an underlying role for biological drivers in addition to socioeconomic and environmental factors.

Fig. 1.

Annual SEER prostate cancer (PC) mortality rates (left) and incidence rates (right) of selected racial groups (Black, White, Asian/Pacific Islander, All races) in the US per 100,000 people [3]. Prostate cancer incidence and mortality rates have declined over the past twenty years for each racial group, though rates of prostate cancer incidence and mortality remain significantly higher for Black Americans relative to all other racial groups.

Table 1.

Left panel: age-stratified average SEER prostate cancer incidence and mortality rates (per 100,000 people) of selected racial groups (Non-Hispanic White, Black (includes Hispanic), Hispanic (any race), and Asian/Pacific Islander (includes Hispanic)) in the US from 2012–2018 [3]. Right panel: the ratios of prostate cancer incidence and mortality rates in each racial group, relative to Non-Hispanic White incidence/mortality rates. Notably, the Black:White disparities in prostate cancer incidence (2.01 to 1.62 to 1.39) and mortality (2.78 to 2.58 to 1.96) decrease in severity as the groups increase in age, suggesting the racial disparity is more severe among younger (< 65 years old) Black men. SEER prostate cancer incidence and mortality rates are lower in Hispanic men compared to White men (all ratios ≤ 1), and lowest in Asian/Pacific Islander men compared to White men (all ratios ≤ 0.70).

	2012–2018 Average PC Incidence*					Ratios of PC Incidence, Relative to Non-Hispanic White
		White(Non-Hispanic)	Black (includes Hispanic)	Hispanic(any race)	Asian/Pacific Islander (includes Hispanic)	White: White Ratio	Black: White Ratio	Hispanic: White Ratio	Asian/PI: White Ratio
*Rate per 100,000	Ages 40–64	123.9	248.9	95.4	53.3	1.0	2.01	0.77	0.43
	Ages 65–74	651.6	1055.5	581.6	376.7	1.0	1.62	0.89	0.58
	Ages 75+	492.5	686.7	482.6	337.2	1.0	1.39	0.98	0.68
	2012–2018 Average PC Mortality*					Ratios of PC Mortality, Relative to Non-Hispanic White
		White(Non-Hispanic)	Black (includes Hispanic)	Hispanic(any race)	Asian/Pacific Islander (includes Hispanic)	White: White Ratio	Black: White Ratio	Hispanic: White Ratio	Asian/PI: White Ratio
*Rate per 100,000	Ages 40–64	4.1	11.4	3.7	1.6	1.0	2.78	0.90	0.40
	Ages 65–74	48.2	124.5	43.2	20.2	1.0	2.58	0.90	0.42
	Ages 75+	224.5	440.5	195.9	113.8	1.0	1.96	0.87	0.51

In this mini review, we will first briefly examine the non-biological determinants of prostate cancer health disparities to facilitate a discussion on the interplay between the socioeconomic inequities and genomics in driving prostate cancer disparities. We aim to provide an up-to-date summary of the biological drivers of prostate cancer by race/ethnicity and discuss how future studies can improve precision oncology and alleviate prostate cancer health disparities.

2. Socioeconomic and healthcare inequities are key determinants of prostate cancer disparities, but do not fully explain observed disparities

A multitude of data supports the hypothesis that systemic discrimination and socioeconomic differences are major drivers of prostate cancer disparities.

2.1. Incidence and mortality rates by race and socioeconomic status

In the United States, Black men are 1.76 times more likely to be diagnosed and 2.14 times more likely to die from prostate cancer compared to White men. Black men are also more likely to have a more advanced stage of prostate cancer at the time of diagnosis [4,5]. According to United States health coverage statistics, in 2019, 9.6% of Black men were uninsured, compared to 16.7% of Hispanic men and 5.2% of non-Hispanic White men [6]. Notably, while both Black men and Hispanic men experience significant barriers in accessing healthcare, prostate cancer incidence and mortality levels in Black men are the highest of all races/ethnic group. he same disparity is not observed in Hispanic men (Table 1). This is perhaps partially due to the socioeconomic barriers that are not identical for Black and Hispanic men. The socioeconomic effects/lifestyle consequences may also vary by race and therefore may affect Black men more than Hispanic men. Importantly, prostate cancer incidence and mortality in Hispanic men is not only lower compared to Black men but is also lower compared to non-Hispanic White men, hinting at a role for biological factors in driving disparate outcomes. If access to care and socioeconomic status solely drove prostate cancer disparities, then we would not expect lower prostate cancer mortality in Hispanic men compared to Black and White men (Table 1).

Two analyses of prostate cancer outcomes showed prostate cancer mortality rates decrease for White men as SES increases, but mortality rates do not decrease for Black men as SES increases [7,8]. This provides further evidence, though geographically limited, that SES alone does not fully account for disparate outcomes in prostate cancer and highlights the importance of other sociological and biological factors (Fig. 2). We conclude there is a biological component contributing to disparate outcomes in prostate cancer and review key racial-biological differences in sections 4–7 of this review.

Fig. 2.

Determinants of Racial Disparities in Prostate Cancer. A multitude of complex parameters including social factors (e.g., access to healthcare, diet), economic factors (e.g., cost of healthcare), environmental factors (e.g., metal toxicity), and biological factors (e.g., family history, genetic and epigenetic alterations) collectively contribute to increased incidence and mortality rates of prostate cancer in Black men compared to men of other races/ethnicities.

2.2. Survival rates in an equal-access medical system

To determine whether an equal-access medical system can attenuate the disparities observed by race, multiple retrospective studies have focused on the Veterans Affairs (VA) United States healthcare system. Riviere and team recently carried out one of the largest analyses to date using a centralized database of >20 million veterans. They assembled a cohort of 60,035 veterans diagnosed with prostate cancer (30.3% Black men and 69.7% non-Hispanic White men) and found that the overall survival rate in Black men was similar to that of non-Hispanic White men [9]. Similar observations have been made in other smaller VA cohorts by other investigators [10–12]. Retrospective studies evaluating the impact of access to healthcare on survival are limited outside of the VA system. A handful of studies have noted that the racial disparity in prostate cancer mortality diminishes among patients age 65+ and among patients with Medicare coverage; however, cohort sizes were small [13, 14]. A multiple-cohort study by Dess et al. with over 300,000 Prostate Cancer patients found that, relative to White men, Black men with nonmetastatic prostate cancer had similar prostate cancer specific mortality in a setting with equal access to care and a standardized treatment regimen [15]. Collectively, these studies highlight that helping to ensure equal access to healthcare for every patient will be a major way to increase survival benefits for all races.

It is important to note that many of these VA-centric studies focused on survival rate and stage at diagnosis in men with prostate cancer and do not provide an estimate of incidence rate. Survival rate is determined by the natural history of the disease (i.e., stage at diagnosis and therapeutic efficacy). Consequently, survival rate is highly sensitive to availability of cancer screening and treatment options. Incidence and mortality rates, on the other hand, are estimates of a disease burden at the population level (i.e., overall veteran population), which is excluded from VA-centric studies.

2.3. Limitations to prostate cancer screening

Incidence rates are also driven by availability of screening. For example, in 2012, the US Preventive Services Task Force (USPSTF) released a recommendation against PSA-based screening for prostate cancer (Grade D recommendation). Following the USPSTF recommendation, the Behavioral Risk Factor Surveillance System reported significant decreases in PSA screening (9.3% among non-Hispanic Whites, 11.6% among non-Hispanic Black, and 7.9% in Hispanics) between 2012 and 2018 [11,12] and concurrently, the incidence ratio of localized prostate cancer in Black men compared to White men increased during this period. A marked reduction was also noted in the number of prostate biopsies performed and in the diagnosis of low-risk, intermediate-risk, and high-risk prostate cancer in the US [13]. Most importantly, a considerably higher prostate cancer mortality rate was observed in Black men in this timeframe [14,16]. Prior studies have illustrated that Black men with prostate cancer were younger at diagnosis and presented with higher PSA levels at diagnosis compared to White men [5]. It is important to note here that prostate cancer health disparities studies often adjust for stage or grade of disease in an attempt to adjust for disparities in screening.

Keeping these limitations in mind, according to the Automated Central Tumor Registry (ACTUR) of the Department of Defense, the incidence of prostate cancer in military men (between 20 and 59 years of age), irrespective of race, continued to be twice that of the general population [17]. Military men with exposure to Agent Orange and other battlefield chemicals often present with more aggressive prostate cancer [18]. Other studies have also reported that Black men are still more likely to have higher Gleason scores and PSA levels than their White counterparts in equal access settings [12,19,20]. These recurrent observations highlight that, even with equal access to care, there is an underlying difference in prostate cancer biology across different races and an early onset of prostate cancer in Black men that warrants further exploration.

3. Interplay between non-biological and biological factors of health disparities and current limitations

Studies have illustrated that disease-related loci in prostate cancer in Black men display higher prevalence of DNA hypermethylation compared to other races [21,22]. However, assessment of how epigenetic imprinting is influenced by socioeconomic status is yet to be determined. As we move forward, it is important to keep in mind that the biological and the non-biological determinants of prostate cancer are two sides of the same coin.

3.1. Limitations in availability of diverse biological specimens

The impact of non-biological determinants of prostate cancer on incidence, mortality, and survival have been the focus of epidemiological research for decades. Substantial advances in geographical information systems (GISs) now provide greater spatial/geographical context to these studies. On the other hand, comprehensive, large-scale studies of biological determinants are far fewer and incomplete, and do not incorporate individual-level socioeconomic status. Importantly, investigation of biological determinants depends on access to biospecimens from a diverse population of patients. The vast majority of previously published studies aimed at identifying biological drivers of prostate cancer health disparities had limited biospecimens from diverse patients. Most frequently, biospecimens are obtained in a clinical setting and require willingness of the patients to participate in clinical trials and/or donating biological specimens to biorepositories for molecular analysis. A major barrier in prostate cancer research is low enrollment of Black men in clinical trials. A recent study by Rencsok and team of 72 global Phase II and IV clinical trials (with 893,378 participants) conducted between 1987 and 2016 found that 96% of total pooled participants were White, while Africans and Caribbeans comprised only 3% of the participants [23]. A similar study looking at metastatic castration resistant prostate cancer (mCRPC) clinical trials within the US also found that Black men were grossly underrepresented in clinical trials, making up a mere 3.3% of the total trial participants (other racial minorities were also vastly underrepresented ≤0.5%) [24]. This lack of participation can be attributed to disproportionate hurdles faced by Black men including, but not limited to: poverty, access to transportation, healthcare, childcare, and knowledge about clinical trials [25]. As others have highlighted, low accrual into clinical trials is a product of lack of access, financial burden of follow-up meetings and/or lab testing not covered by the trial, historical mistrust of the healthcare system, and catchment area of trials amongst other factors [24,26]. Despite advancement in technological tools for rapidly analyzing biospecimens and reduction in sequencing costs, we continue to be limited in our studies due to low access to biospecimens from diverse groups.

This limitation is primely exemplified in a recent seminal genome-wide association study (largest of its kind) carried out by Haiman and colleagues. The researchers calculated a genetic risk score (GRS) of 269 risk variants in 107,247 prostate cancer cases and 127,006 controls and found that the mean GRS in Black men was 2.18 times higher than that of White men while Asian men had 0.73 times lower association than White men [27]. The researchers note that this level of high mean GRS score in Black men has not been consistently observed in other cancers across multi-center studies and is likely seen in prostate cancer because of a strong genetic component to the disease. The group identified 86 novel, independent genetic risk loci of which 32 were significantly associated with prostate cancer in White men. However, only 5 new risk loci were identified for Asian men and only 1 for Black men. Identification of risk loci in Black men was limited due to the cohort size (Black man constituted less than 10% of the cohort) yet again emphasizing the need for enrollment of non-White men in clinical trials to identify additional risk variants.

3.2. Limitations in ancestral characterization

A major confounding factor in understanding the biological drivers of prostate cancer health disparities is the classification of study participants using only self-reported ‘race’ (which is more of a social construct than biology) and not genetic variation or ancestry [28]. An overwhelming majority of the currently available studies lack sequencing-driven genetic ancestry data. A recent genomic study, aimed at understanding how prostate cancer genomes differed by self-reported race and genetic ancestry, found that clinical factors and cancer risk factors differed noticeably by self-reported race and ancestry [29]. Thus, equalizing access to care is unlikely to fully eliminate racial disparities and a more meaningful understanding of the common drivers of prostate cancer in various ancestry groups are critical to eliminating inequities in prostate cancer. Through genetic ancestry analysis, in a recent study, Kittles and colleagues illustrated that some commercially available “African American” prostate cancer cell lines (based on self-identified race), such as E006AA-hT, carry 91% European genetic ancestry [28]. Another widely advertised ‘mixed’ race prostate cancer cell line, 22Rv1, was shown to carry 99% European ancestry. Therefore, as we recognize the need for additional samples and model systems to conduct molecular biology research of health disparities, it is imperative that such models are accurately categorized based on genetic ancestry to facilitate meaningful research.

With these limitations in mind, we now shift our attention to discussing key findings from multiple large-scale comparative studies highlighting differences in gene and pathway alteration across racial groups and their implications.

4. Genetic and molecular basis of health disparities in prostate cancer

Histological and large-scale genomic data illustrate that prostate cancer is highly heterogeneous at the individual and population levels, and this diversity contributes to both phenotypic and functional plasticity. We hypothesize that biological factors play a critical role in the early onset of prostate cancer in Black men and as well as the aggressive nature of the disease (i.e., resistance to available therapeutics). As such, biological factors are critical influencers of prostate cancer incidence, survival, and mortality rate.

4.1. Androgen receptor signaling

The androgen receptor (AR) is a ligand-regulated transcription factor that plays a central role in the development and function of the normal prostate as well as in initiation and progression of prostate cancer (Fig. 3) [30]. Ligands that stimulate AR signaling include testosterone and dihydrotestosterone (DHT).

Fig. 3.

Androgen receptor (AR)-mediated regulation of prostate cancer. Directionality of the arrows (up = increase, down = decrease) and font color (red = increase, green = decrease) indicate the expression level of these drivers in Black men compared to White men with prostate cancer. Canonical AR signaling is mediated through androgen binding AR in the cytoplasm, which leads to a conformational change in AR causing it to dimerize. Upon dimerization, AR translocates to the nucleus and binds to androgen response elements (ARE) to allow transcription of many cancer-related genes. In Black men with prostate cancer, PSA and c-Myc levels are higher and TMPRSS2/ERG fusion rates are lower compared to White men with prostate cancer. A non-canonical AR signaling pathway mediated through PI3K and Akt also regulates AR signaling via phosphorylation. Many components of the PI3K pathway are upregulated in Black men with prostate cancer, including increased serum levels of growth factors, increased MNX1 activity, and preferential deletion of RGS12, leading to higher transcription of lipid metabolism genes such as SREBP1 and FASN.

4.1.1. Increased AR protein and AR ligand in Black men

Several studies have reported that Black men have higher (as much as 4.9% higher) free testosterone levels compared to White men [31]. Studies have also reported increased AR protein levels in prostate cancer in Black men relative to White men, even after normalization for Gleason score [32,33] as well as increased somatic and germline hyper-mutation of AR in Black men with prostate cancer [34].

4.1.2. Presence of shorter CAG repeats in Black men

A notable alteration in the AR gene is the length of the polymorphic cytosine, adenine, guanine (CAG) repeat sequence in Exon 1 of AR, which encodes the N-terminal transactivation domain. CAG repeat/PolyQ tract length is inversely correlated with AR transcriptional activity (Fig. 3), risk of developing prostate cancer, and being diagnosed with a more advanced stage of prostate cancer [35,36]. Multiple clinical studies have unequivocally established that the length of CAG repeats in men of African ancestry is significantly shorter compared to other races (with and without prostate cancer) [37–39]. Shorter length of CAG repeats have been correlated with more aggressive disease in some studies [37,40,41].

4.1.3. AR splice variants

Emergence of post-transcriptional AR splice variants (i.e., AR-v7 and AR-v567) following castration have been linked to resistance and aggressive disease in White men [42], while the role of the AR splice variants in prostate cancer in Black men remains elusive. In a recent study, Armstrong and group assessed AR-v7 status in a cohort of 98 mCRPC using one of the two assays [43]. Within this cohort, 23% of Black men and 29% of White men tested positive for the AR-v7 splice variant. In a second study conducted by Tagawa and colleagues, AR splice variant was detectable in 90% of White men and 86% of Black men with mCRPC [44]. Both studies are confounded by low representation of Black men in these studies (5 Black men in the Armstrong study and 8 Black men in the Tagawa study).

4.1.4. Vitamin D deficiency in Black men

Interestingly, studies have highlighted strong association between Vitamin D deficiency and increased prostate cancer aggressiveness, mortality, and disparity [45–48]. The expression of megalin (LRP2), an endocytic membrane receptor that imports globulin-bound Vitamin D, is significantly increased in men of West African ancestry [49] (Fig. 3). Megalin-mediated import of androgens, which drive prostate cancer tumorigenesis via AR, likely highlights a compensatory response in prostate tissue to Vitamin D deficiency in Black men. This critical role for Vitamin D in driving prostate cancer aggressiveness was further highlighted in a recent race-stratified study that illustrated that Vitamin D intake above Recommended Dietary Allowance is inversely associated with high risk and high grade prostate cancer in Black men but not in White men [50].

Collectively, these studies highlight an important role for the AR signaling axis in driving prostate cancer health disparities. Yet, many questions remain unanswered. Does AR transcriptional output vary across different ancestral groups? Prior studies have demonstrated that the AR cistrome can be extensively reprogrammed during prostate cancer tumorigenesis and disease progression in White men, however, how AR cistromes vary across ancestral groups is not known.

4.1.5. Clinical response to AR signaling inhibitors in Black men

In the first ever prospective multicenter study stratified by race (NCT01940276), George and colleagues found that, relative to White men with mCRPC, Black men are more likely to have greater and more durable PSA responses to a combination of abiraterone acetate (Zytiga) and prednisone [51]. Abiraterone acetate is a selective, irreversible inhibitor of CYP17 and can suppress adrenal synthesis of androgen precursors as well as in situ steroidogenesis in the tumor microenvironment. In the Abi race trial, the median time to PSA progression in Black men was 16.6 months compared to 11.5 months in White men. Interestingly, radiographic progression-free survival (rPFS) and median overall survival (OS) were the same in Black and White men. Whether this is due to the presence of alternative, ligand independent AR activation mechanisms in prostate cancer in Black men remains to be determined.

4.2. Lower occurrence of TMPRSS2-ETS fusion and PTEN deletion in Black men

The most common genomic alteration in prostate cancer is the fusion of the 5′-UTR of TMPRSS2 (21q22) with the 3′-end of ETS family members, such as ERG (21q22), ETV1 (7p21), ETV4 (17q21), or ETV5 (3q27). Multiple studies have confirmed that the TMPRSS2:ERG gene fusion is significantly less common in prostate cancer in Black men (29.3% Black vs. 39.6% White) [52]. Notably, TMPRSS2:ERG fusion positive prostate cancer in White men is often enriched for PTEN loss. Similar to TMPRSS2:ERG fusion, the loss of PTEN is far less common in Black men (11.5% in Black men vs. 30.2% in White men) [52]. A recent study in Black men from South Africa, reported that low frequency of TMPRSS2:ERG fusion was significantly associated with early onset of low-grade prostate cancer presentation, with higher expression from distal ERG junction coordinates [53]. Further studies are warranted to understand why (and how) the frequency of these fusion events are reduced in Black men and how that contributes to early onset of prostate cancer.

4.3. Increased alteration in FOXA1 in Black men

Forkhead box A1 (FOXA1) is a pioneer transcription factor that promotes AR binding and transcriptional activity and is required for normal development of the prostate gland [54,55]. In a cohort of 2393 primary prostate cancer patients, (2109 White, 204 Black, 80 Asian), FOXA1 mutations were shown to be more frequent in Black men compared to White men (18.6% vs. 11.9%) [56]. The functional consequences of these mutations remain to be fully determined, although they likely result in an increased activation of the AR signaling axis. Notably, a recent study of Asian men reported high frequency of FOXA1 missense mutation that resulted in non-functional protein or indel that resulted in frame-shift deletion [57]. Whether these genomic changes are associated with improved prostate cancer survival in Asian men has not been determined.

4.4. Increased alterations in SPOP and CHD1 in Black men

Somatic missense mutations in the speckle-type pox virus and zinc finger (POZ) protein (SPOP) gene occur frequently and early in prostate carcinogenesis and define a genomically distinct class of prostate cancer. SPOP is an adaptor for the Cullin 3 (Cul3)/Rbx1 E3 ubiquitin ligase system and is important for ubiquitination and subsequent degradation of several oncoproteins, including AR and many of its co-regulators [58–60]. Prostate cancer-associated SPOP mutations disrupt its ability to bind substrates and promote their degradation, resulting in a dominant-negative protein that causes dysregulation of several major signaling pathways and cellular processes in prostate cancer [60]. SPOP mutations frequently co-occur with CHD1 (chromodomain helicase DNA binding protein 1) deletions but are mutually exclusive with TMPRSS2-ERG rearrangements [59]. Loss of CHD1 results in altered chromatin occupancy of AR and promotes oncogenic AR-driven transcription [61]. Emerging data suggest that CHD1 deletion events are higher in Black men than in White men [62]. Multiple groups have reported higher frequency of SPOP mutations in prostate cancer in Black men compared to White men, [52,63,64], though other studies have observed similar frequency of SPOP mutations in Black men and White men [65].

The higher frequency of SPOP mutations and potentially of CHD1 deletions in prostate cancer in Black men have multiple implications. As SPOP mutations occur early in prostate tumorigenesis, they may contribute to early onset of an aggressive prostate cancer observed clinically in Black men. Second, in clinical settings, SPOP mutation and CHD1 deletion may be used as biomarkers. Both SPOP and CHD1 are important modulators of DNA damage repair and alterations in these genes can result in increased DNA damage repair via the error-prone non-homologous end joining (NHEJ) pathway, which increases mutational burden in prostate cancer [66,67]. Recently, poly-ADP ribose polymerase (PARP) inhibitors (olaparib, rucaparib, and niraparib) were approved for the treatment of homologous repair-deficient mCRPC. However, PARP inhibitor treatment decisions are currently solely driven by mutations in a small panel of homologous recombination repair (HRR) genes. Prior preclinical studies have suggested that SPOP mutation and/or CHD1 loss can result in increased sensitivity to PARP and other DNA damage response inhibitors (such as (ataxia telangiectasia and Rad3-related) ATR inhibitors) [68]. Retrospective clinical data analysis evaluating performance of PARP inhibitors across racial groups have not been published yet. Further studies are warranted to determine whether SPOP mutation and CHD1 loss can be used as additional biomarkers in decision making steps for PARP inhibitors and other DNA damage repair (DDR) inhibitors.

5. Racial disparities in DNA damage and genomic instability in prostate cancer

Germline mutations in DNA repair genes are associated with higher risk of developing prostate cancer and more aggressive prostate cancer [69–71]. In primary and metastatic prostate cancer, germline mutations are common in BRCA1 and BRCA2 genes; loss-of-function mutations in BRCA1/2 lead to a deficiency in error-free homologous recombination (HR) repair (Fig. 4). Importantly, BRCA mutations are currently the best predictor of response to platinum-based chemotherapy [72] and PARP inhibitors [73]. Multiple recent studies reported a higher rate of BRCA2 (2.8-fold higher) mutations in Black men compared to White men, including one study where protein-truncating unique BRCA2 mutations were identified in Black men with early-onset of prostate cancer [74,75]. Aside from mutations in HRR genes, frequent mutations have also been reported in nucleotide excision repair pathway (NER) genes in Black men with prostate cancer (at least one mutation in NER genes in 89% of tumors) [76]. On the other hand, mutations in mismatch repair pathway (MMR) genes, MutS homolog 2 and 6 (MSH2 and MSH6) [77] and TP53 [29] were less common in Black men. Aside from DNA repair pathway gene mutations, dysfunctional telomeres are a major source for genomic instability. The guanine rich nucleotides in telomeres are susceptible to oxidative damage by reactive oxygen species [78] and mutations in DNA damage repair pathways can result in telomere shortening [79]. Further, leukocyte telomere length was reported to be shorter in high grade prostate cancer in Black men and was associated with aggressive disease and biochemical recurrence after radical prostatectomy and radio-therapy [80,81].

Fig. 4.

Mutations in DNA repair genes occur more frequently in Black men with prostate cancer compared to White men (22.5% vs 15.6%). DNA damage in prostate cells causes activation of DNA repair pathways such as homologous recombination (HR), non-homologous end joining (NHEJ), alternative end joining (a-EJ), and single-strand annealing (SSA) via AR signaling. NHEJ, a-EJ, and SSA are considered error-prone pathways, whereas HR is considered error-free. Black men have increased rates of SPOP mutations (SPOP^mut) compared to White men. SPOP mutations increase the rate of NHEJ, leading to more error-prone DNA repair. PARP inhibitors have been approved for use in patients with deleterious HR gene (BRCA1/2) mutations. Given the similarity between HR gene mutations and SPOP mutations (both resulting in error-prone DNA damage repair), PARP inhibitors have the potential to also benefit prostate cancer patients with SPOP mutations.

Genetic alterations can also result from a combination of exogenous insults, such as X-rays, ultraviolet light, and various chemicals (i.e., polycyclic aromatic hydrocarbons (PAHs)), and endogenous assaults from reactive oxygen species (ROS) and other reactive metabolites. Recent prospective studies have shown that high levels of PAH-DNA adducts (from cigarette smoke exposure and/or charred meat) significantly increase the risk of prostate cancer development in Black men but not in White men [82,83]. Studies have also reported race specific polymorphisms in several enzymes (CYP1A1 Ile462Val, CYP1B1 A119S and L432V, mEH Tyr113His and His139Arg, CYP3A4 A(−392)G) and glutathione S-transferases (GSTs)) that are critical for metabolism of PAHs and detoxication of the primary and dihydrodiol epoxides of PAHs [84]. Notably, polymorphism in GST (GSTT1 null genotype) increased risk of biochemical recurrence of prostate cancer in Black men [84]. In sum, increased genomic instability in Black men with prostate cancer driven by modulators of DNA damage recognition or repair protein and/or exogenous factors highlight potential utility of biomarkers in delivering targeted therapy which can improve overall survival of Black men with prostate cancer.

6. Racial disparities in metabolic dysregulation in aggressive prostate cancer

High-fat diet and obesity are strongly associated with prostate cancer incidence and progression, while increased lipogenesis and uptake of exogenous lipids are linked to prostate cancer aggressiveness and recurrence [85–88]. Increased prostatic total and free fatty acids correlate with higher occurrence, progression, and worse prostate cancer outcomes in Black men, compared to other racial groups [89]. Rapidly proliferating cancer cells also upregulate de novo lipogenesis, even in the presence of exogenous fatty acid, to provide lipids for membrane formation, protein lipidation, intratumoral androgen synthesis, and to support energy production via β-oxidation [90]. Relative to White men, Black men with prostate cancer have increased expression of essential de novo lipogenesis genes such as SREBP1/2, FASN, stearoyl-CoA desaturases, α-methylacyl-CoA racemase, and acetyl-CoA carboxylase (Fig. 3) [91–93]. Overexpression of SREBP1 and FASN is associated with tumor aggressiveness, poor clinical outcomes, and drug resistance through dysregulation of lipid metabolism [94]. We have previously illustrated that MNX1, a homeobox transcription factor, is expressed at a significantly higher level in Black men with prostate cancer compared to their White counterparts, and MNX1 upregulates lipid synthesis by stimulating expression of SREBP1 and fatty acid synthetase (Fig. 3) [95]. In addition, MNX1 and de novo lipogenesis pathways are regulated by AKT signaling, which is almost universally upregulated in advanced prostate cancer and linked to prostate cancer progression, worse patient outcomes, and therapeutic resistance [96, 97]. This upregulation is frequently a consequence of loss of PTEN, a dual protein/lipid phosphatase and an important negative regulator of PI3K-AKT-mTOR signaling. Notably, in Black men with prostate cancer, PTEN loss is less common (11.5% in Black men vs. 30.2% in White men) [52]. Thus, alternative, novel mechanisms likely result in the constitutive activation of PI3K-AKT-mTOR signaling. Recent mapping of the RNA splicing landscape of prostate cancer across racial populations showed differential splicing events in highly prevalent cancer-associated genes and pathways [98]. Specific splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 have been shown to enhance AKT/mTOR signaling and increase proliferative and invasive capacity of prostate cancer in Black men [98], suggesting differential splicing is a driver of PI3K-AKT-mTOR signaling. Notably, RGS12, a recently identified negative regulator of MNX1 and AKT signaling that is located on chromosome 4p16.3, is preferentially deleted in prostate cancer in Black men [99]. Thus, altered genomic and epigenomic signaling, resulting in enhanced activation of oncogenic signaling and alternative metabolism can potentially drive tumor cell transformation into a more aggressive prostate cancer. Importantly, multiple preclinical studies of inhibitors targeting lipogenesis have consistently illustrated a decrease in AR protein and its transcriptional output [100,101], suggesting that targeting tumor fat metabolism will likely increase efficacy of current FDA-approved anti-androgens (such as enzalutamide and abiraterone) and taxanes, particularly in Black men with prostate cancer. This latter hypothesis remains to be tested under a clinical trial setting.

7. Racial disparities and the prostate tumor microenvironment

Socioeconomic factors (such as stress and diet) can result in heightened oxidative stress and increased inflammatory reactivity, which contributes disease risk and burden. Recent studies have reported significant differences in immune and inflammatory pathways between prostate cancer in Black and White patients and suggest that increased inflammation in the tumor microenvironment (TME) of prostate cancer in Black men is a driver of disparate clinical outcomes [102]. Pro-inflammatory cytokine genes, including CXCR4, IL6, IL8, TNF, IL1β, and MMP9 (Fig. 5) show higher expression in prostate cancer in Black men compared to White men [103,104]. CXCR4–CXCL12 signaling is interconnected with central prostate cancer oncogenic signaling and the promotion of prostate cancer metastasis, highlighting its potential as a biomarker for inflammation and metastasis in prostate cancer in Black men [105]. Interleukin-6 (IL6) and IL8 are known activators of AR signaling and are associated with resistance to androgen deprivation therapy in prostate cancer [104]. TNF-alpha and IL1β activate both CXCR4 and matrix metalloproteinases (MMPs) including MMP9, leading to epithelial-mesenchymal transition (EMT) and metastasis in prostate cancer cells [106]. Moreover, Black men with prostate cancer have higher serum levels of TGFβ3 compared to White men. Notably, serum TGFβ3 levels were higher in Black men without prostate cancer than levels in White men with prostate cancer. Collectively, these studies highlight significant differences in tumor microenvironment between Black and White men.

Fig. 5.

Most upregulated immune/inflammation genes in prostate cancer in Black men have proinflammatory functions, as opposed to immunosuppressive. Genes in red are upregulated in prostate cancer in Black men relative to White men. Some key cell subpopulations involved in immunosuppressive signaling are shown, including regulatory T cells (Treg), tumor-associated macrophages (TAM), and myeloid-derived suppressor cells (MDSC). During carcinogenesis, stromal fibroblasts differentiate into cancer-associated myofibroblasts. As key members of the prostate tumor microenvironment, both fibroblasts and myofibroblasts express proinflammatory cytokines, such as IL6, IL8, TNF, TGFβ, and IL1β (all of which are expressed at higher rates in prostate cancer in Black men compared to prostate cancer in White men).

Consistent with these observed biological differences within the TME, oncogenic signaling, and immunologic pathways, recent retrospective analysis of PROCEED (PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data; NCT01306890) found increased overall survival in Black men with mCRPC compared with White men with prostate cancer when treated with sipuleucel-T, an autologous cellular immunotherapy [107,108]. Inhibitors of transforming growth factors (TGFs) in mCRPC are being actively evaluated in clinical trials [109]. Whether TGFβ3-targeting therapies will have a greater benefit in Black men with prostate cancer remains to be seen.

The studies highlighted in the above section outline important differences in prostate cancer among men of different ancestry. These differences are likely to affect disease emergence, aggressiveness, detection and response to therapy, and ultimately patient survival.

8. Concluding remarks

Prostate cancer incidence and mortality vary across racial groups, with Black men carrying the greatest burden, the causes of which are complex. In 2015, the Precision Medicine Initiative began, aiming to enhance the understanding of the genetic and environmental determinants of disease in clinical settings across the United States. As discussed in this brief review, ancestry-related differences in genomic alterations, gene expression, epigenetic modifications, tumor metabolism, tumor microenvironment, and immunogenicity are likely contributors of disparities in prostate cancer across racial groups and will undoubtedly impact how we develop new precision therapeutic interventions. Studies on biology and access to healthcare similarly highlight the need for increased representation of men from underserved racial groups, particularly Black men, in translational and clinical research to fully comprehend and appreciate the tumor heterogeneity. This lack of participation in clinical and translational research can be attributed to disparate barriers faced by Black men such as poverty, access to transportation, healthcare, childcare, and clinical trial education [25]. Future studies are warranted using SNP-based ancestry stratification in early-onset and metastatic prostate cancer. Further-more, understanding that prostate cancer in Black men is different from prostate cancer in White men in terms of transcriptome is not enough. To facilitate meaningful clinical advances, we must identify master regulators that drive these differences.

Translational laboratory research often focuses on validating and informing clinical observations using disease models (i.e., providing molecular mechanisms). This research suffers from a severe lack of racially diverse prostate cancer models. Currently, there are approximately 200 prostate cancer cell lines (including parental lines and their derivatives) that originate from White men, and only five from Black men. As noted elsewhere in this review, commercially available models can be incorrectly characterized. Future translational health disparities research will require development of pre-clinical models, such as genetically engineered mouse models, patient derived xenograft (PDX) models, and most recently, ex-vivo organoid models, which will facilitate and improve the development and testing of experimental therapeutics. In addition to generating novel models, researchers must be willing to share newly established models with the community to maximize impact. Despite reports of approximately 120 prostate cancer PDX models in the literature, only a handful are available to the research community to facilitate translational research, and none are from men of African ancestry [110]. Establishing national biorepositories can significantly empower the community of prostate cancer health disparities investigators. To this end, we draw our reader’s attention to the following resource for novel cancer models supported by the Nation Cancer Institute: https://portal.pdxnetwork.org/.

It is abundantly clear that racial disparities in prostate cancer are a result of a complex system. We further propose that biological factors play a critical role in early onset of prostate cancer in Black men. As such, biological factors are critical influencers of prostate cancer incidence, age at onset, survival, and mortality rate. However, such biological differences are not solely genetic or predetermined, but rather can be a result of physiological response to psychosocial stressors, such as racism and segregation. This phenomenon can be further explained by the “Weathering Hypothesis” which states exposure to chronic stress can cause premature decline in one’s physical health [111,112]. Additionally, Black men experience higher allostatic load (the cumulative burden of chronic stress and life events), and a 2006 study by Coker et al., showed higher John Henryism (in which individuals cope with stress with over-performance) scores indicating high-effort coping that may be associated with an increase in prostate cancer risk [112,113]. These interactions, which ultimately affect physical health, can partially explain the racial disparity in PC, though further work is required to quantify causality. Therefore, future prostate cancer health disparities research must prioritize interdisciplinary multicenter studies to promote meaningful and quality health disparities research. An emerging body of work in cancer health disparities research strongly supports an important role for socioeconomic status on epigenetic imprinting, higher inflammatory signature [114], changes in DNA methylation status [115], and epigenetic aging [116]. These and other studies raise a horrifying concern that systemic racism and social inequalities not only kill cancer patients due to lack of access to healthcare but importantly, structural racism may leave behind heritable imprints. Unfortunately, studies bridging social determinants with epigenetic processes remain sparse or completely lacking for certain racial groups. It is broadly recognized that the drivers of health disparities in prostate cancer are multifaceted and complex. To truly tackle this problem, researchers must emerge from their silos to develop adequate infrastructure to conduct multi-center, multi-omics studies that incorporate multidimensional geocoded census data and precise, individual-level data [117]. Ultimately, funding agencies, prostate cancer researchers, healthcare providers, and patients must recognize all aspects of prostate cancer health disparities and collaborate to drive more comprehensive studies under relevant conditions and models to mitigate prostate cancer health disparities.

Significance.

Black men in the US are 1.76 times more likely to be diagnosed with prostate cancer and 2.14 times more likely to die from prostate cancer compared to White men. Ensuring equal access to quality healthcare is vital in addressing racial disparities in prostate cancer but is unlikely to completely eliminate these disparities, as significant differences have been observed in prostate cancer biology between various ancestral groups. Multi-center, interdisciplinary research is urgently needed to bridge the gap between the social determinants and biological factors of health disparities in prostate cancer. Increasing racial diversity in pre-clinical (patient-derived cell and xenograft) models and clinical trials is necessary to further the field’s understanding of the intra-racial and inter-racial heterogeneity of prostate carcinogenesis.

Abbreviations:

ATR

ataxia telangiectasia and Rad3-related

GSTs

glutathione S-transferases

PAHs

polycyclic aromatic hydrocarbons

TME

tumor microenvironment

EMT

epithelial-mesenchymal transition

TGF

transforming growth factor

PDX

patient derived xenograft

AR

androgen receptor

NEPC

neuroendocrine prostate cancer

CRPC

castration-resistant prostate cancer

mCRPC

metastatic castration-resistant prostate cancer

PARP

Poly(ADP-ribose) polymerase

NER

nucleotide excision repair

DDR

DNA damage repair

MMR

mismatch repair

HRR

homologous recombination repair

NHEJ

non-homologous end joining

UTR

untranslated region

ETS

erythroblast transformation specific