Skip to main content
NCBI home page
Molecular Endocrinology logoLink to Molecular Endocrinology
. 2013 Apr 22;27(6):879–891. doi: 10.1210/me.2013-1039

Minireview: The Molecular and Genomic Basis for Prostate Cancer Health Disparities

Isaac J Powell 1,✉, Aliccia Bollig-Fischer 1
PMCID: PMC5415277  PMID: 23608645

Abstract

Despite more aggressive screening across all demographics and gradual declines in mortality related to prostate cancer (PCa) in the United States, race disparities persist. For African American men (AAM), PCa is more often an aggressive disease showing increased metastases and greater PCa-related mortality compared with European American men. The earliest research points to how distinctions are likely the result of a combination of factors, including ancestry genetics and lifestyle variables. More recent research considers that cancer, although influenced by external forces, is ultimately a disease primarily driven by aberrations observed in the molecular genetics of the tumor. Research studying PCa predominantly from European American men shows that indolent and advanced or metastatic prostate tumors have distinguishing molecular genomic make-ups. Early yet increasing evidence suggests that clinically distinct PCa from AAM also display molecular distinctions. It is reasonable to predict that further study will reveal molecular subtypes and various frequencies for PCa subtypes among diverse patient groups, thereby providing insight as to the genomic lesions and gene signatures that are functionally implicated in carcinogenesis or aggressive PCa in AAM. That knowledge will prove useful in developing strategies to predict who will develop advanced PCa among AAM and will provide the rationale to develop effective individualized treatment strategies to overcome disparities.

The incidence of prostate cancer (PCa) is approximately 60% higher, and the mortality rate is 2 to 3 times greater among African American men (AAM) compared with European American men (EAM). These findings have been consistent for more than 20 years, before and after the prostate-specific antigen (PSA) testing era (1). Men of West African ancestry from the Caribbean and South America share similar incidence and mortality to African Americans, suggesting a possible genetic basis for these outcomes (2). However, there are probably multiple factors contributing to these disparities.

Lack of access to care has been suggested as being responsible for disproportionate advanced disease and mortality among AAM in comparison with EAM. Data from the Behavioral Risk Factor Surveillance Study indicate that in recent years, AAM are as likely to be tested for PCa by PSA as are EAM, 59.6% vs 55.5%, respectively (3). However, AAM continue to present with more advanced disease and higher mortality rates. Financial barriers or the lack of insurance has also been suggested as potential causes for the disparity. According to the Behavioral Risk Factor Surveillance Study, the insurance rates for AAM and EAM over the age of 50 years is 81% and 89%, respectively (3). That difference is statistically significant but, in our opinion, does not account for the entire disparity, and perhaps it may only contribute to a small difference in access to care as demonstrated by the similar rate of PSA testing.

Socio-economic status (SES) has also been reported as a contributing factor for PCa racial disparity, but this issue is controversial. Studies that examined SES in a multivariable analysis have demonstrated that SES does contribute to racial outcome disparity (4). However, no difference in PCa recurrence after radical prostatectomy (RP) was identified among AAM when lower income vs middle income was compared (5). Nonfinancial barriers, such as poor health seeking behavior, have been reported to delay diagnosis of PCa among AAM. Along these lines, bias against aggressive diagnostic and treatment strategies, or fear of the diagnosis of PCa and distrust of the health care system, appear to be the most dominant factors (6).

We reported that a faster PCa growth rate and/or an earlier transformation from latent to aggressive PCa among AAM compared with EAM contributes significantly to the racial disparity of advanced disease at diagnosis, and to the 2 to 3 times greater mortality rate among AAM vs EAM (6–8). We examined an autopsy series and RP data at Wayne State University and the Karmanos Cancer Institute, as well as the Detroit Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data to study this issue. The autopsy study of 1056 men who died from causes other than PCa between 1993 and 2004 indicates that PCa initiation occurs as early as ages 20–29 and that the prevalence is similar for all ages in AAM and EAM (summarized in Table 1). Furthermore, the prevalence of mostly latent or subclinical PCas at autopsy increases with age as we would expect, and the prevalence continues to be similar between the 2 races (8).

Table 1.

Incidence of Prostate Cancer in Autopsy Specimens from Men Who Died of Unrelated Causes, Detroit, Michigan 1993–2004

Age group Specimen number
 PCa
AAM EAM AAM EAM
20–29 156 30 8% 11%
30–39 130 76 31% 31%
40–49 178 130 43% 38%
50–59 111 103 46% 44%
60–69 34 54 72% 68%
70–79 21 33 77% 69%
Open in a new tab

The autopsy volume of PCa among AAM is similar to EAM for ages 20–60 years, and grade is similar for ages 20–70 years. However, PCa volume of RP specimens demonstrates greater tumor volume among AAM compared with EAM ages 39–70 years, although EAM have greater volume of PCa than AAM in both the autopsy and RP specimens among even older men. For men age 40–69, AAM have a marginally higher Gleason grade (6 or lower vs 7 or higher) when compared with EAM (P = .0562) (8); in the 6-year span from 1992 to 1998, higher Gleason grade in AAM compared with EAM was highly significant (P = .028). From the Detroit SEER data, the age-specific incidence rates for distant PCa per 100 000 men are approximately 4 times greater among AAM compared with EAM across all age groups (summarized in Table 2). If PCa starts at the same time as demonstrated in our autopsy study, but reaches distant metastasis at a rate approximately 3-fold or greater for AAM compared with EAM, then one may also conclude that PCa progresses faster in AAM than in EAM.

Table 2.

Incidence of Invasive Distant Stage Cancer in Men Diagnosed with Prostate Cancer

Age at diagnosis EAM rate AAM rate Rate ratio Ratio P value
40–49 0.7 2.5 3.67 <.0001
50–59 5.4 15.9 2.63 <.0001
60–69 19.7 58.3 2.73 <.0001
70–79 44.7 109.1 2.26 <.0001
Open in a new tab

Rates per 100 000 men according to Detroit SEER-Medicare-linked data, years 1995–2007.

Because tumor volume and grade are reflections of the biology of PCa, the analysis implies that PCa in AAM is biologically and genetically more aggressive compared with EAM. Cancer is ultimately a genetic disease, involving patient genetics and aberrant tumor genomics. Therefore, the pursuit of an explanation for differences in incidence and disease progression should begin there. In this article, we review the growing body of evidence to suggest that molecular and genome-based distinctions are associated with, or contribute to, PCa health disparities for AAM.

Inherited Risk Alleles

The question of whether or not an inherited genetic predisposition may contribute to the higher PCa incidence and mortality rate seen in AAM has been the focus of many research studies, and various germ-line susceptibility loci are reported. Corroborating results from independent research groups provide especially compelling support for specific risk loci in the CYP3A4 and EphB2 genes, and in the 8q24 chromosomal region.

The CYP3A4 single nucleotide polymorphism (SNP)

The CYP3A4 gene translates to an enzyme belonging to the cytochrome P-450 family that functions in the oxidative deactivation of testosterone to biologically less active metabolites (9, 10). Research suggests that this process is disrupted by a germ-line SNP in the 5′ regulatory region of the CYP3A4 gene consisting of an adenine to guanine allelic variant. Referred to as CYP3A4*1B, and alternatively as CYP3A4-V or CYP3A4-392A>G, it was discovered to be associated with a higher clinical grade and stage in a study of non-Hispanic Caucasian men with PCa (11). Later, it was determined that the frequency of the G allele was differentially distributed across populations distinguished by race or ethnicity, such that the G allele is more often found in AAM than in EAM, Hispanic, or Asian American men (12, 13).

To study the impact of this polymorphism on risk of PCa recurrence after prostatectomy in AAM and EAM, we assembled clinical data and analyzed specimens from a large series of prostatectomy patients, including 428 EAM and 309 AAM, who were carefully staged at a single institution and had 5–10 years of prospective clinical follow-up. Investigation of this cohort demonstrated that the distribution of AA, AG, and GG alleles is strongly associated with race, with 92% of EAM having the AA allele compared with 17% of AAM. The homozygous GG allele and heterozygous AG allele proportions are 1% and 7% among EAM vs 43% and 39% among AAM (13). Further analyses, including all men, showed a significant association between the CYP3A4*1B genotype and recurrence. Moreover, EAM expressing homozygous GG or heterozygous AG had a significantly increased risk of recurrence according to a dose model and by comparison with the AA genotype (13). The strong associations between race and CYP3A4*1B genotype and previously demonstrated poorer survival of AAM compared with EAM in this series ultimately made it impossible to infer whether the G allele is exerting a functional effect or whether it is a surrogate for race in this analysis (13–15).

In a separate case-control study, we examined the association between the CYP3A4*1B variant and the diagnosis or risk of PCa and clinical presentation of PCa. Our analyses controlled for age, body mass index, a family history of PCa, and history of benign prostatic hyperplasia and stratified subjects by age at diagnosis and clinical characteristics at presentation. Here, among AAM, the CYP3A4*1B genotype was strongly associated with PCa that had aggressive characteristics at diagnosis (16). All told, the findings suggest that the CYP3A4*1B variant is associated with aggressive disease and progression in EAM and AAM, but it occurs with greater frequency in AAM.

Despite the abundance of evidence for the statistical significance of the CYP3A4*1B variant in PCa, it is not yet obvious how its discovery can impact current therapeutic strategies. Androgen-dependent signaling is presently the target of traditional first-line therapy for the disease. Moreover, treatment strategies would remain unchanged even if follow-up research reinforced evidence that it was linked to more aggressive PCa phenotype in AAM, where it is observed most frequently. We do however project that continued genomic research of PCa will show molecular subtypes that are driven by various oncogenes independent of androgen signaling, much as it did for breast cancer and estrogen receptor signaling. If this prediction plays out, then further research may be called for to show whether CYP3A4*1B is a viable marker to elevate the importance of continued androgen ablation for a patient, or to predict the level of responsiveness to targeting androgen-dependent signaling for a particular patient when a new variety of treatment options exist.

8q24 Region alleles

Amundadottir et al (17) were among the first to report on an allelic variant on chromosome 8q24 that contributes to a heritable risk of PCa. Specifically, they report that allele −8 of the microsatellite DG8S737 is associated with PCa based on an investigation of 3 case-control series of European ancestry from Iceland, Sweden, and the United States showing an estimated odds ratio (OR) of the allele at 1.62 with approximately 19% of affected men and 13% of the general population carry at least 1 copy, yielding a population attributable risk of −8%. In addition, they discovered the association in an African American case-control group where 41% of affected individuals and 30% of the population are carriers; reporting an OR similar to that for European ancestry, but a greater estimated population attributable risk (16%) that may contribute to higher incidence of PCa in AAM than in men of European ancestry (17). Freedman et al (18) also report the significance of an association for a 3.8-Mb interval in chromosome 8q24 and risk for PCa in AAM. Their study pointed to the existence of additional relevant SNPs in the region and showed that the increased risk is greater in men diagnosed before age 72. This is in agreement with the epidemiological observation that the higher risk for PCa in African Americans is greatest in younger men and decreases with age (18). A follow-up study identified an additional 7 SNPs within the 8q24 region that are associated with significantly higher risk estimates among AAM than EAM (19). Additional independent studies confirmed the associations for African American ancestry and PCa susceptibility loci in the chromosome 8q24 region (20, 21).

It is less well established that chromosome 8q24-localized allelic variants are associated with PCa aggressiveness, but it should be noted that Helfand et al (22) reported that the presence of multiple risk alleles was significantly associated with high-grade disease in biopsy and prostatectomy specimens. In addition, the Broad11934905 A risk allele, found only in patients of African ancestry, is significantly associated with higher pathologic stage, and patients with this allele demonstrate increased frequency of biochemical recurrence and shorter time to biochemical recurrence compared with patients without the allele (23).

Broadly speaking, the statistical meaningfulness for allelic variation in the 8q24 region has been reported and validated by independent researchers (24). However, the significant 8q24 variants do not map to known genes nor do they alter the coding sequence of a protein (19). Until functional evidence for how any specific allele in this region impacts PCa risk or aggressiveness is presented, it remains unclear how exactly this line of research will translate to identify a putative patient population and, moreover, how it will inform intervention or treatment strategies.

EphB2 SNPs

The EphB2 tyrosine kinase was first reported as a PCa tumor suppressor gene, harboring somatic mutations in prostate tumors (26). Additionally, a germ-line EPHB2 nonsense variant (3055A.T; K1019X) was positively associated with risk of familial PCa in AAM from high-risk families (27). Robbins et al (28) set out to test the hypothesis that common variation within the EphB2 locus is associated with increased risk of sporadic PCa in AAM. They genotyped 341 SNPs within the EphB2 gene in 490 sporadic PCa cases and 567 matched controls from AAM. Seven EphB2 SNPs showed a statistically significant association with PCa risk, among them, the most significant association was achieved for a synonymous coding SNP, referred to as TGen-624. Two SNPs showed significant associations toward a protective effect, those were rs10465543 and rs12090415 with an OR of 0.49 and 0.7, respectively. Haplotype analysis revealed low levels of linkage disequilibrium within the region, with 2 blocks being associated with PCa risk (28).

Oncogenes and Tumor Suppressors

Although germ-line susceptibility alleles may play a role, carcinogenesis and cancer progression are ultimately pathological processes mechanistically driven by an aberrant tumor genome. Thus, the tumor genome exhibits the causes for initiation and the course of progression of the disease, and various cancer types are divided into molecular subtypes that harbor key oncogenes and tumor suppressors that inform cancer treatment strategies (29, 30). Decades of research and the success of targeted treatments support the understanding that cancer driver genes, referred to as oncogenes, are activated by amplification, overexpression, gain-of-function mutations, or genomic rearrangements (reviewed in Refs. 31, 32). Tumor suppressors, those genes that otherwise slow normal cell growth processes or promote tissue differentiation, are inactivated by genomic lesions linked to loss-of-function.

Comprehensive molecular subtyping of prostate tumors remains to be completed. However, recent studies have identified recurring significant mutations, gene rearrangements, DNA amplifications and losses, and dysregulated methylation in the PCa genome and related aberrant gene expression (33–35). Although most of the work to date describes a limited population in terms of patient diversity, growing evidence from studies of DNA methylation, cytogenomics, and gene expression analysis of tumors from diverse populations supports the idea that PCa disparities are related to observable distinctions in the molecular make-up of the tumor. Moreover, groundbreaking work in the study of breast cancer demonstrated that the prevalence of specific molecular subtypes differs for populations comprising AAM or EAM (36, 37); further research will tell whether the same is observed for PCa.

Evidence of DNA damage preceding disease in AAM

Genetic lesions, including genomic rearrangements, mutations, and gains and losses that are implicated in carcinogenesis and cancer progression, result from accumulating DNA damage. One mechanism among many that may contribute to DNA damage at tumor sites, including in the prostate gland, involves exposure to environmental chemical carcinogens (38); chemical carcinogens react with DNA bases to form bulky DNA adducts that disrupt the DNA replication and repair processes leading to strand breaks and mutations (39). Recent research suggests that higher rates of incidence for PCa in AAM compared with EAM may be linked to higher levels of DNA adducts formed by polycyclic aromatic hydrocarbons (PAHs), particularly benzo(a)pyrene adducts in AAM (40, 41). Tang et al (41) used an immunohistochemical approach to measure PAH-DNA adduct levels in 536 benign prostate specimens from a diverse population of men who at the time of had no history of PCa (59% EAM and 41% AAM). Modeling the analysis with follow-up diagnostic data showed that elevated adduct levels were significantly associated with increased risk of disease in AAM but not EAM (41). Moreover, the association of high PAH-adduct levels in PCa and cancer risk was greatest for occurrence of disease in AAM within 4 years of the first, benign biopsy (41).

Studies by Nock et al (40, 42) provide evidence that carcinogen exposure is not the only variable to consider in this process that leads to cancer gene mutations. Importantly, racial differences exist for genetic variation in PAH-metabolizing enzymes, such as cytochrome P450 CYP1B1 and glutathione S-transferase (40, 42). The decreased efficiency of these enzymes and repair processes impacted by allelic polymorphisms can be directly linked to observations of high levels of DNA adducts and mutations (40, 42).

Taken together, the evidence surrounding deregulation of DNA damage mechanisms from studies of diverse populations supports their function as a contributing factor to PCa disparities, although it is clear that additional work in this area is needed. There are other chemical carcinogen-dependent processes with different modes of action that remain to be studied or for which early results warrant further study. For example, a single study of healthy participants by Watters et al (43) reports that oxidation of DNA is greater in EAM than AAM and is linked to dietary considerations. Also, for the purpose of translating this area of study to PCa therapies, it will be important to clarify specifics pertaining to the impact a certain carcinogen and/or DNA damage mechanism is having on molecular drivers or cancer-specific signaling and population-specific clinical outcomes.

Genomic gains and losses in prostate tumors from AAM

Genomic gains and losses are relevant to the functional status of many known oncogenes and tumor suppressors, and recent research points to specific aberrations that are significantly represented in PCa. Presently, copy number variations can be detected by a number of robust methods, including most recently new algorithms to analyze exome sequencing data (35). Copy number variations are not always associated with gene expression changes (44). Therefore, the importance or functional consequence for gains or losses at a specific locus is inferred from analysis that associates copy number changes with gene expression changes. One of the earliest studies comparing PCa from AAM and EAM with the aim to uncover copy number variations used an analytical approach referred to as arrayed comparative genomic hybridization (aCGH). This method can, by comparison of tumor DNA with appropriate DNA controls, detect gains or losses in copy numbers of genes or DNA regions that are specific to tumors. The particular study used a low resolution variation of the method, where 1247 oligonucleotide probes targeting DNA sequence were evenly distributed across the genome (45), and results showed that similar patterns of chromosome alterations existed in clinically localized PCa from AAM and EAM (45). However, a report of a mixed population study of advanced disease, which used similar low resolution techniques, describes evidence of significant higher frequency of amplification within the 4q25-q28 region in tumors from AAM who developed an androgen deprivation-resistant recurrence or metastatic cancer (46).

A later study used a SNP array profiling method to analyze tumors of all stages from AAM and by comparison with previous published data from tumors of EAM concluded that the frequencies for gains and losses in localized PCa from AAM compared with lesions discovered in metastatic PCa from EAM (47). A more recent report describes that bacterial artificial chromosome-based aCGH analyses of PCa from AAM and EAM identified 27 chromosomal regions that were more commonly altered in localized prostate tumor specimens from either AAM (n = 20) or EAM (n = 21) that were grade, stage, and age matched (48). Copy number changes in these 27 regions correlated with gene expression differences (48). Moreover, the study authors rediscovered 4 of the regions using an alternative high-resolution oligonucleotide-based aCGH method (average spatial resolution of ∼9 kb) in follow-up analysis of a substantially larger independent validation cohort. The 4 chromosomal regions of interest include: 3q26.1 showing loss in AAM; and 5p15.33, 14q32.33, and 16p11.2 showing gain in AAM, specifically. According to functional annotation analysis, genes in these regions were enriched for the ontological category of Immune System Processes. This list of genes included IL-27, ITGAL, ITGAM, ITGAD, IGHM, SPN, LAT, and AKT1, which showed amplification and higher expression in tumors from AAM (48).

It is clear that the lack of corroborating results among the few papers that describe genomic profiles across diverse populations are mostly due to limits of sample size and differences in methodologies. The inroads made with analytical improvements stress that continued work to examine genes activated or inactivated by amplification or loss could yield candidate genes demonstrating aberrant copy numbers and expression levels that are specific to a subpopulation of AAM.

PCa gene mutations

What is known to date about mutations in PCa comes largely from recent reports of high-throughput, massively parallel sequencing of genomes and exomes of PCa specimens derived from EAM (35). This work demonstrates that significant mutations in PCa occur with similar frequency as in other organ sites. Furthermore, significant recurring mutations were observed in primary localized and treatment-resistant metastatic disease (35). Among those identified in localized and metastatic disease were inactivating mutations for phosphatase and tensin homolog and tumor protein p53 tumor suppressors and, interestingly, genes with a role in regulating androgen receptor (AR) signaling, eg, forkhead box protein A1 and cyclin dependent kinase N1B (35), raising the possibility that a subset of early staged tumors harbor a determinant for antiandrogen treatment resistance. Genes that were significantly mutated in castration-resistant metastatic disease and not in localized disease included among others AR, CDK12, and retinoblastoma protein (35).

Glaringly absent in the present literature are similar comprehensive reports to detail the mutations of genes in PCa tumors from AAM, which we know to have clinical distinctions. Nevertheless, based on the most recent results, related questions are emerging for disparities research. Do similar mutations occur with equal frequency in PCa from AAM at different stages; or do differences account for more rapid progression of disease in AAM?

Gene rearrangements in the PCa genome associated with AAM

The story for gene rearrangements in PCa has taken center stage with evidence that at least half of PCa specimens have DNA rearrangements involving the fusion of an androgen-responsive gene promoter region with genes of the E-twenty six (ETS) family of transcription factors, such as v-ets erythroblastosis virus E26 oncogene homolog (ERG) predominantly and to a lesser extent ETS variant 1 (49–52). The functional consequence of the rearrangement, by either chromosomal translocation or deletion, is the up-regulation of expression and accompanying oncogenic activation of the transcription factor. Two groups have recently suggested alternative mechanisms that are each mutually exclusive of ETS rearrangement events that drive the other half of prostate tumors (33, 53).

Here again, however, the PCa story is incomplete; simply, research of specimens from AAM were not included in these studies, and the comparable work in AAM remains to be done. Moreover, evidence exists to suggest that PCa from AAM do not similarly fit so simply into this developing paradigm of PCa molecular subtyping. Among the limited research into PCa from AAM and expression of TMPRSS2-ERG fusions, Magi-Galluzzi et al (52) examined 42 and 64 PCa specimens from EAM and AAM, respectively, for prevalence of the translocation event, and the results showed a significant difference in frequencies of detection. The analysis found the gene fusion in 50% of PCa from EAM and 31% of PCa from AAM. They also analyzed PCa from Japanese Americans, where the rate of discovery was 16%. A multivariate analysis demonstrated that expression of TMPRSS2-ERG correlated with ethnicity, and with less significance correlated with the pathologic stage; there were no correlations with other clinical parameters, including age, PSA levels, and Gleason score. Consistent with this report, results of our own work to compare gene expression levels in clinically localized tumors from AAM and EAM showed significantly higher ERG expression in specimens from EAM (54). This gene-level result coincides with results from a recently published study showing that ERG protein-positive prostate tumors were significantly greater in EAM compared with AAM (55).

Prostate Cancer Epigenetics

Cancer-specific gene expression and the activity of cancer-promoting signaling networks are highly influenced by cancer-associated derangement of epigenetic marks on DNA and posttranslational modifications of histone proteins associated with DNA that affect gene expression and gene variant expression. A wide variety of epigenetic marks, such as acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, are documented to play important and often complicated roles in regulating the expression of genes in cancers of all types, including PCa (reviewed in Ref. 56).

A well-studied epigenetic event in PCa is hypermethylation of CpG islands in the DNA promoter region of the glutathione S-transferase gene GSTP1, which translates to an enzyme that plays a role in turnover or reduction of chemical carcinogens and reactive oxygen species (57). Independent reports agree that hypermethylation of the GSTP1 promoter, with the effect of repressing GSTP1 expression, is present in 90% of PCa specimens analyzed (58). This is a far greater frequency than any DNA mutation event discovered and could be relevant for early PCa detection. Research aiming to discover differential promoter methylation in localized PCa compared with metastatic PCa showed significant hypermethylation of promoters for GSTP1, APC, RASSF1a, COX2, and MDR1 genes in both localized and metastatic disease, but the significance for hypermethylation of ER-α, hMLH1, and p14/INK4a promoters was associated only with metastatic disease (59). Studies have compared GSTP1 hypermethylation in PCa from AAM and EAM and found that levels across the 2 populations were similar (58, 60). However, based on the function of GSTP1 enzyme, it has been proposed that hypermethylation of the GSTP1 gene promoter causes greater susceptibility to the effects of dietary and lifestyle variables that do distinguish populations (61). Kwabi-Addo et al (58) report that the promoters of cancer-linked genes TIMP3 and NKX2–5 are hypermethylated and expression repressed in PCa from both AAM and EAM. Interestingly, these promoters were hypermethylated in normal prostate tissue from AAM only.

Results from numerous reports advance the hypothesis that the epigenetic marks differ for localized and advanced diseases (34, 59), yet few studies have explored the role of epigenetics in the PCa phenotypes observed for AAM that have a more rapidly advancing disease. All told, it is evident that tumor epigenetics is an important issue to consider in the molecular study of PCa disparities, and it remains to be adequately studied.

Prostate Tumor Transcriptome

As stated above, the increased incidence PCa and PCa-related risk of death observed for AAM are likely due to a combination of factors, including genetic predisposition or ancestry, lifestyle, and patient bias against aggressive diagnostic and treatment strategies (6, 62–64). Furthermore, evidence is presented here that links underlying reasons for the aggressive phenotype to molecular mechanisms and PCa genetics. By the very nature of biological signaling processes, the combined effects of these factors for aggressive or advanced cancer in AAM will be reflected in the tumor transcriptome (summarized in Figure 1). Early evidence for differential gene expression across PCa specimens from AAM and EAM supports this assumption.

Figure 1.

Figure 1.

Open in a new tab

The diagram highlights current understanding that the effects of ancestry genetics, environment, and lifestyle are likely collective causes for aggressive PCa in AAM. Moreover, they, along with somatic tumor-specific molecular genetics, play a role in shaping the tumor transcriptome.

The epidermal growth factor receptor (EGFR) is an oncogene that is reported to be overexpressed more often in PCa from AAM compared with EAM (65, 66); however, it is not found to be amplified in the PCa genome in AAM. In vitro and in vivo studies have demonstrated that EGFR protein kinase can promote PCa phenotypes, including the androgen-independent growth phenotype (67–71). A report of a missense mutation for EGFR occurring only in PCa from EAM also points to racial differences (72), but analysis of greater numbers of specimens from AAM may overturn this finding, just as a similar story has unfolded for lung cancer (73). A class of anticancer agents targeting the EGFR protein already exists and although clinical efforts have failed to see a benefit from EGFR-targeted treatment for PCa (74), continued study for a more complete molecular definition of an EGFR-driven PCa subtype could more effectively guide treatment and yield clinical benefits for individual patients.

In one of the first whole genome microarray expression studies to compare PCa from AAM and EAM, a very limited number of clinically matched samples were analyzed and demonstrated broader gene expression differences across the 2 populations (75). From the comparison of 8 PCa specimens from EAM and 8 AAM, a set of 67 genes showed significant expression level differences. Based on ontological enrichment analysis, the set of genes was enriched for genes associated with IL signaling (75). Another study analyzed gene expression in 33 and 36 PCa specimens from AAM and EAM, respectively, and matched normal specimens by microarray (76). From their analysis, Wallace et al (76) identified that 162 transcripts were differentially expressed in PCa from AAM and EAM. Systems-level analysis of the set of differentially expressed genes found a significant disease relationship with autoimmunity and inflammation. Pathway-level analysis significantly linked the differentially expressed genes to immune response, stress response, cytokine signaling, and chemotaxis pathways. Key discoveries were that metastasis-promoting genes, including autocrine mobility factor receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), and matrix metalloproteinase 9 (MMP9), were more highly expressed in PCa from AAM than in PCa from EAM (76).

Our own more recent work, representing the largest cohort to date, analyzed clinically localized tumors from 270 AAM and 369 EAM using a custom microarray consisting multiple probes targeting each of 517 genes, selected for their known importance in PCa or cancer in general (54). The results were revealing and consistent with work by others in a number of ways. The analysis focused in on a total of 95 genes showing significantly greater expression in PCa from AAM (54). Among them, AKT-1 expression was significantly higher in PCa from AAM compared with EAM, which is consistent with the work by Rose et al (48), who demonstrated amplification and overexpression of the gene in PCa from AAM. As stated previously, our analysis also identified decreased ERG expression in PCa from AAM compared with EAM, which is consistent with findings for less frequent ETS translocation events in PCa in AAM (52). The analysis also identified that CXCR4, FASN, BMP2, and NFKB1 gene expression was higher in PCa from AAM, in addition to inflammatory cytokines IL-6, IL-8, and IL-1B (54).

Finally, noncoding RNA transcripts are also found to be differentially expressed among PCa specimens from AAM and EAM and are likely to have functional consequences. PCGEM1 is one example so far, shown to be significantly higher in PCa from AAM compared with PCa of EAM (77). Prostate cell line-based evidence shows this transcript to promote proliferation and colony formation in soft agar, 2 measures of its oncogenic potential (77).

Nuclear Hormone Receptors

Androgen receptor

Normal cell division in the prostate gland is largely regulated by androgen analogues binding to and activating the AR protein and aberrant androgen signaling promotes PCa (reviewed in Ref. 78). Above we briefly presented evidence to suggest that aberrant androgen-dependent signaling also plays a role in PCa disparities. Specifically, the CYP3A4*1B germ-line allele causes impaired function in the oxidative deactivation of testosterone to biologically less active metabolites, and it is more frequently identified in AAM. Furthermore, others have shown that AAM may have higher levels of AR in both healthy prostate and PCa tissues (79). It is postulated that these observations are linked to a greater incidence of PCa and more aggressive PCa in AAM. However, this association remains to be unequivocally demonstrated to be causally implicated.

The observation of a polymorphic CAG repeat sequence in the AR gene directly impacts AR activity and may also have some bearing on differences for PCa biology in AAM and EAM. This CAG repeat sequence, which varies in length from approximately 8 to 31 repeats, encodes for a polyglutamine chain in the C-terminal AR transactivation domain (80). As a result, a long CAG repeat sequence is inhibitory to AR function (81, 82). For men with and without PCa, frequency of shorter CAG repeats is reported to be higher in AAM than in EAM (83, 84). However, it appears that this CAG repeat length does not significantly associate with a disease phenotype or risk in AAM (83, 85). In stark contrast, shorter repeats were found to predict higher grade and advanced stage at diagnosis, metastases, and mortality from the disease in EAM (86). Studies are contrasting regarding whether or not fewer repeats are associated with higher risk in EAM (86, 87). Adding another layer of complexity, a mixed population study associated long CAG repeats with increased risk of recurrence irrespective of race (88), although a substantially larger study, involving predominantly EAM, found no association (89). Although studies are differing and contrasting, perhaps the results do hint at fundamental differences in the molecular biology of tumors from AAM and EAM that we have yet to appreciate.

The prevalence of TMPRSS2-ETS fusion expression in PCa from AAM and EAM deserves special attention. As stated briefly above, a TMPRSS2-ETS oncogenic lesion unites an androgen-responsive promoter region and an ETS family transcription factor (49–52). The rearrangement causes the androgen-dependent, up-regulated expression of the transcription factor. In the case of ERG, the event is driven by a 21q22.2-3 chromosomal deletion. For other ETS transcription factors, up-regulation is due to the translocation of a chromosomal region. An early study reported that TMPRSS2-ERG fusion was more common in PCa from AAM than EAM (47). The study was hindered for reasons that they used a SNP array-based method to analyze specimens from AAM and compared their data with results from another study of PCa in EAM that used aCGH (90). Neither of the methods detects copy number neutral translocations. A following study used fluorescent in situ hybridization methods, able to detect the various forms of the lesion, and reported that the overall rate was in fact lower in PCa from AAM (52). Studies reporting lower ERG gene expression and protein levels concur with the results from fluorescent in situ hybridization analyses (54, 55).

The high frequency of oncogenic gene rearrangements involving the fusion of an androgen-responsive gene promoter region with genes of the ETS family of transcription factors (ie, ERG fusion genes) specifically in PCa from EAM suggests that androgen signaling has an important role in promoting PCa in both EAM and AAM. Nevertheless, investigations should continue to explore whether or how a unique gene expression program is activated by androgen signaling in PCa from AAM compared with EAM (91). The issue of whether or not AR activation by androgen-independent mechanisms contributes to PCa race disparities also deserves much warranted attention. Numerous studies have reported AR mRNA splicing variants and other alternative mechanisms of AR activation in castrate-resistant PCa, ie, androgen-independent AR function (92–97). Studies have neglected to examine the mechanisms in PCa cells derived from AAM, and race has not been a consideration in relevant population studies.

Vitamin D receptor (VDR)

Vitamin D and the VDR protein have also reached a level of importance in the literature surrounding PCa disparities. A recent notable study involving predominantly EAM demonstrates that high plasma levels of the active form of vitamin D, 25-hydroxyvitamin D, is associated with a decreased risk of lethal PCa (98). The same study also identified that multimarker SNP sets linked to 7 vitamin D pathway-related genes, including VDR, were associated with PCa risk. The study did not research whether the associations hold true for AAM, although men of high-level African ancestry are shown to have lower vitamin D levels than EAM or men estimated to have lower levels of African ancestry (99). In our own analysis of VDR polymorphisms in 428 EAM and 310 AAM who underwent RP, carefully staged and followed for 5–10 years, we identified that a single VDR polymorphism, the BsmI B allele, was protective against recurrence in EAM but not in AAM (100). Based on these collective findings, it is compelling to hypothesize that decreased VDR signaling contributes to the greater risk of advanced or lethal disease in the African American population, certainly more research in this area to include AAM is called for.

Influencing Factors Outside of the Tumor

Tumor microenvironment

The tumor microenvironment plays a significant role in influencing PCa development and progression to advanced metastatic disease (101–103). Furthermore, functional genomic studies highlight a variety of molecular mechanisms that explain how the surrounding stromal influences tumor-specific gene expression and protein translation to affect tumor biology (101, 104). Important work also demonstrates the capacity for the microenvironment presented at the site of distal metastases to play a role in PCa metastases to bone (102).

These studies and others like them did not include a mixed race cohort and could not address the potential for molecular differences in the tumor stroma of AAM compared with EAM. However, evidence for differences surrounding local and advanced disease in EAM support the hypothesis that the microenvironment factors into phenotypic differences observed in PCa in AAM compared with EAM; for example, the greater incidence of bone metastases in AAM. Although direct evidence is lacking, researchers have inferred microenvironment differences from pathway-level and disease association analyses of differential tumor gene expression data, where a set of genes mostly showing significantly higher levels of expression in PCa from AAM was enriched for pathways and processes related to immune response, inflammatory response, and cytokine signaling (76), it was further reasoned by the authors that pathway activating immunologic or cytokine factors would originate from the tumor stroma.

Patient hypertension, obesity, and inflammation

In our own study of tumor gene expression, we find similar evidence for increased cytokine signaling in PCa from AAM compared with PCa from EAM (54). We have considered that this observation along with other evidence may be pointing to how general patient pathophysiology, beyond the tumor stroma, may be impacting PCa disparities. AAM have been reported to have a higher fat content diet (106) and have a higher rate of hypertension than EAM (107); also, there is a greater prevalence of obesity among AAM with PCa (108). Obesity is associated with increased systemic inflammatory cytokines, which promote oxidative stress that can promote a number of cancer pathways and DNA mutations (109). Also, it has been reported that a diet high in fat content is associated with advanced PCa (110). Increased FASN expression is associated with both lethal PCa and a high-fat diet and high body mass index (111); and our data shows increased FASN expression in PCa from AAM compared with EAM (54). Currently direct mechanistic evidence is lacking, but we predict that further research will show how aberrant expression of key PCa genes and activation of specific cancer signaling pathways is influenced by obesity, hypertension, and inflammation that are more prevalent in AAM.

Concluding Remarks

Data overwhelmingly support that clinical measures indicative of a disproportionate PCa burden in AAM are likely due to a combination of factors, including genetic predisposition or ancestry, lifestyle, and patient resistance toward aggressive diagnostic and treatment strategies (6, 62–64). Here, we have reviewed a growing body of evidence that advances the understanding that molecular mechanisms and the tumor genome and tumor gene expression features are interrelated, perhaps even causally related, with the underlying reasons for PCa health disparities (25, 58, 76, 105). More so, this review underscores that even though AAM experience a greater incidence of disease and present more aggressive disease compared with EAM, studies have traditionally neglected to analyze PCa from AAM.

In comparison with the molecular and genomic understanding and development of related targeted treatment options for other cancers, such as breast, the molecular and genomic study of PCa is in its early stages. However, research advancements now show that indolent and advanced or metastatic prostate tumors have distinguishing molecular make-ups, and corresponding early evidence suggests that clinically distinct PCa from AAM also display molecular distinctions. It is reasonable to predict that further study will reveal molecular subtypes and various frequencies for PCa subtypes among diverse patient groups, as is seen for African American women with breast cancer (37). As it stands, the genomic lesions, or genomic and gene signatures that are functionally implicated in carcinogenesis or advanced and aggressive PCa in AAM, remain to be discovered. That knowledge will be useful in predicting which patients of African American ancestry will develop advanced PCa and will provide the rationale to develop effective individualized treatment strategies to overcome disparities.

Acknowledgments

This work was supported in part by the Department of Defense Contract W81XWH-10-2-0068 awarded to the Karmanos Cancer Institute and administered by the United States Army Medical Research and Materiel Command and the Telemedicine and Advanced Technology Research Center at Fort Detrick (Maryland). The funders had no role in decision to publish or preparation of the manuscript. The views, opinions and/or findings contained in this publication are those of the authors and do not necessarily reflect the views of the Department of Defense and should not be construed as an official Department of Defense/Army position, policy, or decision.

Disclosure Summary: The authors have nothing to disclose.

Footnotes

Abbreviations:
aCGH
arrayed comparative genomic hybridization
AAM
African American men
AR
androgen receptor
EAM
European American men
EGFR
epidermal growth factor receptor
ERG
v-ets erythroblastosis virus E26 oncogene homolog
ETS
E-twenty six
OR
odds ratio
PAH
polycyclic aromatic hydrocarbon
PCa
prostate cancer
PSA
prostate-specific antigen
RP
radical prostatectomy
SEER
Surveillance, Epidemiology, and End Results
SES
socio-economic status
SNP
single nucleotide polymorphism
VDR
vitamin D receptor.

References

  • 1. Horner M , Ries L , Krapcho M , et al. SEER Cancer Statistics Review, 1975–2006. Bethesda, Maryland: National Cancer Institute; 2009. [Google Scholar]
  • 2. Odedina FT , Akinremi TO , Chinegwundoh F , et al. Prostate cancer disparities in Black men of African descent: a comparative literature review of prostate cancer burden among Black men in the United States, Caribbean, United Kingdom, and West Africa. Infect Agent Cancer. 2009;4(suppl 1):S2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Behavioral Risk Factor Surveillance System. Behavioral risk factor surveillance system survey data. In: Prevention CfDCa. Atlanta, Georgia: United States Department of Health and Human Services, Centers for Disease Control and Prevention; 2009. [Google Scholar]
  • 4. Du XL , Fang S , Coker AL , et al. Racial disparity and socioeconomic status in association with survival in older men with local/regional stage prostate carcinoma: findings from a large community-based cohort. Cancer. 2006;106(6):1276–1285. [DOI] [PubMed] [Google Scholar]
  • 5. Dash A , Lee P , Zhou Q , et al. The impact of socioeconomic factors on prostate cancer outcomes in black patients treated with surgery. Urology. 2008;72(3):641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Powell IJ , Heilbrun LK , Sakr W , et al. The predictive value of race as a clinical prognostic factor among patients with clinically localized prostate cancer: a multivariate analysis of positive surgical margins. Urology. 1997;49(5):726–731. [DOI] [PubMed] [Google Scholar]
  • 7. Powell IJ , Banerjee M , Sakr W , et al. Should African-American men be tested for prostate carcinoma at an earlier age than white men? Cancer. 1999;85(2):472–477. [PubMed] [Google Scholar]
  • 8. Powell IJ , Bock CH , Ruterbusch JJ , Sakr W. Evidence supports a faster growth rate and/or earlier transformation to clinically significant prostate cancer in black than in white American men, and influences racial progression and mortality disparity. J Urol. 2010;183(5):1792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Waxman DJ , Lapenson DP , Aoyama T , Gelboin HV , Gonzalez FJ , Korzekwa K. Steroid hormone hydroxylase specificities of eleven cDNA-expressed human cytochrome P450s. Arch Biochem Biophys. 1991;290(1):160–166. [DOI] [PubMed] [Google Scholar]
  • 10. Ozdemir V , Kalow W , Tang BK , et al. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics. 2000;10(5):373–388. [DOI] [PubMed] [Google Scholar]
  • 11. Rebbeck TR , Jaffe JM , Walker AH , Wein AJ , Malkowicz SB. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst. 1998;90(16):1225–1229. [DOI] [PubMed] [Google Scholar]
  • 12. Paris PL , Kupelian PA , Hall JM , et al. Association between a CYP3A4 genetic variant and clinical presentation in African-American prostate cancer patients. Cancer Epidemiol Biomarkers Prev. 1999;8(10):901–905. [PubMed] [Google Scholar]
  • 13. Powell IJ , Zhou J , Sun Y , et al. CYP3A4 genetic variant and disease-free survival among white and black men after radical prostatectomy. J Urol. 2004;172(5):1848–1852. [DOI] [PubMed] [Google Scholar]
  • 14. Wacholder S , Rothman N , Caporaso N. Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol Biomarkers Prev. 2002;11(6):513–520. [PubMed] [Google Scholar]
  • 15. Powell IJ , Banerjee M , Novallo M , et al. Prostate cancer biochemical recurrence stage for stage is more frequent among African-American than white men with locally advanced but not organ-confined disease. Urology. 2000;55(2):246. [DOI] [PubMed] [Google Scholar]
  • 16. Bangsi D , Zhou JY , Sun Y , et al. Impact of a genetic variant in CYP3A4 on risk and clinical presentation of prostate cancer among white and African-American men. Urol Oncol. 2006;24(1):21. [DOI] [PubMed] [Google Scholar]
  • 17. Amundadottir LT , Sulem P , Gudmundsson J , et al. A common variant associated with prostate cancer in European and African populations. Nat Genet. 2006;38(6):652–658. [DOI] [PubMed] [Google Scholar]
  • 18. Freedman ML , Haiman CA , Patterson N , et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci USA. 2006;103(38):14068–14073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Haiman CA , Patterson N , Freedman ML , et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007;39(5):638–644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Bock CH , Schwartz AG , Ruterbusch JJ , et al. Results from a prostate cancer admixture mapping study in African-American men. Hum Genet. 2009;126(5):637–642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Robbins C , Torres JB , Hooker S , et al. Confirmation study of prostate cancer risk variants at 8q24 in African Americans identifies a novel risk locus. Genome Res. 2007;17(12):1717–1722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Helfand BT , Loeb S , Cashy J , et al. Tumor characteristics of carriers and noncarriers of the deCODE 8q24 prostate cancer susceptibility alleles. J Urol. 2008;179(6):2197–2202. [DOI] [PubMed] [Google Scholar]
  • 23. Whitman EJ , Pomerantz M , Chen Y , et al. Prostate cancer risk allele specific for African descent associates with pathologic stage at prostatectomy. Cancer Epidemiol Biomarkers Prev. 2010;19(1):1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Chang BL , Spangler E , Gallagher S , et al. Validation of genome-wide prostate cancer associations in men of African descent. Cancer Epidemiol Biomarkers Prev. 2011;20(1):23–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Bensen JT , Xu Z , Smith GJ , Mohler JL , Fontham ET , Taylor JA. Genetic polymorphism and prostate cancer aggressiveness: a case-only study of 1,536 GWAS and candidate SNPs in African-Americans and European-Americans. Prostate. 2012;. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Huusko P , Ponciano-Jackson D , Wolf M , et al. Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nat Genet. 2004;36(9):979–983. [DOI] [PubMed] [Google Scholar]
  • 27. Kittles RA , Baffoe-Bonnie AB , Moses TY , et al. A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history. J Med Genet. 2006;43(6):507–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Robbins CM , Hooker S , Kittles RA , Carpten JD. EphB2 SNPs and sporadic prostate cancer risk in African American men. PLoS One. 2011;6(5):e19494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. West L , Vidwans SJ , Campbell NP , et al. A novel classification of lung cancer into molecular subtypes. PLoS One. 2012;7(2):e31906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Sharma SV , Settleman J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007;21(24):3214–3231. [DOI] [PubMed] [Google Scholar]
  • 32. Bild AH , Yao G , Chang JT , et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439(7074):353–357. [DOI] [PubMed] [Google Scholar]
  • 33. Barbieri CE , Baca SC , Lawrence MS , et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44(6):685–689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Friedlander TW , Roy R , Tomlins SA , et al. Common structural and epigenetic changes in the genome of castration-resistant prostate cancer. Cancer Res. 2012;72(3):616–625. [DOI] [PubMed] [Google Scholar]
  • 35. Grasso CS , Wu YM , Robinson DR , et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487(7406):239–243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Stead LA , Lash TL , Sobieraj JE , et al. Triple-negative breast cancers are increased in black women regardless of age or body mass index. Breast Cancer Res. 2009;11(2):R18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Carey LA , Perou CM , Livasy CA , et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492–2502. [DOI] [PubMed] [Google Scholar]
  • 38. Kooiman GG , Martin FL , Williams JA , Grover PL , Phillips DH , Muir GH. The influence of dietary and environmental factors on prostate cancer risk. Prostate Cancer Prostatic Dis. 2000;3(4):256–258. [DOI] [PubMed] [Google Scholar]
  • 39. Hemminki K , Koskinen M , Rajaniemi H , Zhao C. Dna adducts, mutations, and cancer 2000. Regul Toxicol Pharmacol. 2000;32(3):264–275. [DOI] [PubMed] [Google Scholar]
  • 40. Nock NL , Tang D , Rundle A , et al. Associations between smoking, polymorphisms in polycyclic aromatic hydrocarbon (PAH) metabolism and conjugation genes and PAH-DNA adducts in prostate tumors differ by race. Cancer Epidemiol Biomarkers Prev. 2007;16(6):1236–1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Tang D , Kryvenko ON , Wang Y , et al. Elevated polycyclic aromatic hydrocarbon-DNA adducts in benign prostate and risk of prostate cancer in African Americans. Carcinogenesis. 2013;34(1):113–120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Nock NL , Bock C , Neslund-Dudas C , et al. Polymorphisms in glutathione S-transferase genes increase risk of prostate cancer biochemical recurrence differentially by ethnicity and disease severity. Cancer Causes Control. 2009;20(10):1915–1926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Watters JL , Satia JA , Kupper LL , Swenberg JA , Schroeder JC , Switzer BR. Associations of antioxidant nutrients and oxidative DNA damage in healthy African-American and White adults. Cancer Epidemiol Biomarkers Prev. 2007;16(7):1428–1436. [DOI] [PubMed] [Google Scholar]
  • 44. Yang ZQ , Liu G , Bollig-Fischer A , Haddad R , Tarca AL , Ethier SP. Methylation-associated silencing of SFRP1 with an 8p11–12 amplification inhibits canonical and non-canonical WNT pathways in breast cancers. Int J Cancer. 2009;125(7):1613–1621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Cher ML , Lewis PE , Banerjee M , et al. A similar pattern of chromosomal alterations in prostate cancers from African-Americans and Caucasian Americans. Clin Cancer Res. 1998;4(5):1273–1278. [PubMed] [Google Scholar]
  • 46. Cher ML , Bova GS , Moore DH , et al. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res. 1996;56(13):3091–3102. [PubMed] [Google Scholar]
  • 47. Castro P , Creighton CJ , Ozen M , Berel D , Mims MP , Ittmann M. Genomic profiling of prostate cancers from African American men. Neoplasia. 2009;11(3):305–312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Rose AE , Satagopan JM , Oddoux C , et al. Copy number and gene expression differences between African American and Caucasian American prostate cancer. J Transl Med. 2010;8:70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Berger MF , Lawrence MS , Demichelis F , et al. The genomic complexity of primary human prostate cancer. Nature. 2011;470(7333):214–220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Tomlins SA , Laxman B , Dhanasekaran SM , et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007;448(7153):595–599. [DOI] [PubMed] [Google Scholar]
  • 51. Mehra R , Tomlins SA , Shen R , et al. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol. 2007;20(5):538–544. [DOI] [PubMed] [Google Scholar]
  • 52. Magi-Galluzzi C , Tsusuki T , Elson P , et al. TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Caucasian, African-American and Japanese patients. Prostate. 2011;71(5):489–497. [DOI] [PubMed] [Google Scholar]
  • 53. Borno ST , Fischer A , Kerick M , et al. Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. Cancer Discov. 2012;2(11):1024–1035. [DOI] [PubMed] [Google Scholar]
  • 54. Powell I , Dyson G , Land S , et al. Genes associated with prostate cancer are differentially expresed in African American and European American men [published online March 20, 2013]. Cancer Epidemiol Biomarkers Prev. doi:10.1158/1055-9965.EPI-12-1238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Rosen P , Pfister D , Young D , et al. Differences in frequency of ERG oncoprotein expression between index tumors of Caucasian and African American patients with prostate cancer. Urology. 2012;80(4):749–753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Dawson MA , Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27. [DOI] [PubMed] [Google Scholar]
  • 57. Kanwal R , Pandey M , Bhaskaran N , et al. Protection against oxidative DNA damage and stress in human prostate by glutathione S-transferase P1. Mol Carcinog. 2012;. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Kwabi-Addo B , Wang S , Chung W , et al. Identification of differentially methylated genes in normal prostate tissues from African American and Caucasian men. Clin Cancer Res. 2010;16(14):3539–3547. [DOI] [PubMed] [Google Scholar]
  • 59. Yegnasubramanian S , Kowalski J , Gonzalgo ML , et al. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res. 2004;64(6):1975–1986. [DOI] [PubMed] [Google Scholar]
  • 60. Woodson K , Hayes R , Wideroff L , Villaruz L , Tangrea J. Hypermethylation of GSTP1, CD44, and E-cadherin genes in prostate cancer among US Blacks and Whites. Prostate. 2003;55(3):199–205. [DOI] [PubMed] [Google Scholar]
  • 61. Nelson WG , De Marzo AM , Yegnasubramanian S. Epigenetic alterations in human prostate cancers. Endocrinology. 2009;150(9):3991–4002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Major JM , Norman Oliver M , Doubeni CA , Hollenbeck AR , Graubard BI , Sinha R. Socioeconomic status, healthcare density, and risk of prostate cancer among African American and Caucasian men in a large prospective study. Cancer Causes Control. 2012;23(7):1185–1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Hsing AW , Sakoda LC , Chua S. Obesity, metabolic syndrome, and prostate cancer. Am J Clin Nutr. 2007;86(3):s843–s857. [DOI] [PubMed] [Google Scholar]
  • 64. Parker PM , Rice KR , Sterbis JR , et al. Prostate cancer in men less than the age of 50: a comparison of race and outcomes. Urology. 2011;78(1):110–115. [DOI] [PubMed] [Google Scholar]
  • 65. Shuch B , Mikhail M , Satagopan J , et al. Racial disparity of epidermal growth factor receptor expression in prostate cancer. J Clin Oncol. 2004;22(23):4725–4729. [DOI] [PubMed] [Google Scholar]
  • 66. Di Lorenzo G , Tortora G , D'Armiento FP , et al. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res. 2002;8(11):3438–3444. [PubMed] [Google Scholar]
  • 67. Sherwood ER , Van Dongen JL , Wood CG , Liao S , Kozlowski JM , Lee C. Epidermal growth factor receptor activation in androgen-independent but not androgen-stimulated growth of human prostatic carcinoma cells. Br J Cancer. 1998;77(6):855–861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Torring N , Dagnaes-Hansen F , Sorensen BS , Nexo E , Hynes NE. ErbB1 and prostate cancer: ErbB1 activity is essential for androgen-induced proliferation and protection from the apoptotic effects of LY294002. Prostate. 2003;56(2):142–149. [DOI] [PubMed] [Google Scholar]
  • 69. Sirotnak FM , Zakowski MF , Miller VA , Scher HI , Kris MG. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res. 2000;6(12):4885–4892. [PubMed] [Google Scholar]
  • 70. Sirotnak FM , She Y , Lee F , Chen J , Scher HI. Studies with CWR22 xenografts in nude mice suggest that ZD1839 may have a role in the treatment of both androgen-dependent and androgen-independent human prostate cancer. Clin Cancer Res. 2002;8(12):3870–3876. [PubMed] [Google Scholar]
  • 71. Agus DB , Akita RW , Fox WD , et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2(2):127–137. [DOI] [PubMed] [Google Scholar]
  • 72. Douglas DA , Zhong H , Ro JY , et al. Novel mutations of epidermal growth factor receptor in localized prostate cancer. Front Biosci. 2006;11:2518–2525. [DOI] [PubMed] [Google Scholar]
  • 73. Cote ML , Haddad R , Edwards DJ , et al. Frequency and type of epidermal growth factor receptor mutations in African Americans with non-small cell lung cancer. J Thorac Oncol. 2011;6(3):627–630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74. Canil CM , Moore MJ , Winquist E , et al. Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol. 2005;23(3):455–460. [DOI] [PubMed] [Google Scholar]
  • 75. Reams RR , Agrawal D , Davis MB , et al. Microarray comparison of prostate tumor gene expression in African-American and Caucasian American males: a pilot project study. Infect Agent Cancer. 2009;4(suppl 1):S3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76. Wallace TA , Prueitt RL , Yi M , et al. Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res. 2008;68(3):927–936. [DOI] [PubMed] [Google Scholar]
  • 77. Petrovics G , Zhang W , Makarem M , et al. Elevated expression of PCGEM1, a prostate-specific gene with cell growth-promoting function, is associated with high-risk prostate cancer patients. Oncogene. 2004;23(2):605–611. [DOI] [PubMed] [Google Scholar]
  • 78. Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol. 2002;20(13):3001–3015. [DOI] [PubMed] [Google Scholar]
  • 79. Gaston KE , Kim D , Singh S , Ford OH , Mohler JL. Racial differences in androgen receptor protein expression in men with clinically localized prostate cancer. J Urol. 2003;170(3):990–993. [DOI] [PubMed] [Google Scholar]
  • 80. La Spada AR , Wilson EM , Lubahn DB , Harding AE , Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352(6330):77–79. [DOI] [PubMed] [Google Scholar]
  • 81. Chamberlain NL , Driver ED , Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994;22(15):3181–3186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82. Lim HN , Chen H , McBride S , et al. Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males. Hum Mol Genet. 2000;9(5):829–834. [DOI] [PubMed] [Google Scholar]
  • 83. Bennett CL , Price DK , Kim S , et al. Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status. J Clin Oncol. 2002;20(17):3599–3604. [DOI] [PubMed] [Google Scholar]
  • 84. Sartor O , Zheng Q , Eastham JA. Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology. 1999;53(2):378–380. [DOI] [PubMed] [Google Scholar]
  • 85. Gilligan T , Manola J , Sartor O , Weinrich SP , Moul JW , Kantoff PW. Absence of a correlation of androgen receptor gene CAG repeat length and prostate cancer risk in an African-American population. Clin Prostate Cancer. 2004;3(2):98–103. [DOI] [PubMed] [Google Scholar]
  • 86. Giovannucci E , Stampfer MJ , Krithivas K , et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA. 1997;94(7):3320–3323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Chen C , Lamharzi N , Weiss NS , et al. Androgen receptor polymorphisms and the incidence of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2002;11(10 pt 1):1033–1040. [PubMed] [Google Scholar]
  • 88. Powell IJ , Land SJ , Dey J , et al. The impact of CAG repeats in exon 1 of the androgen receptor on disease progression after prostatectomy. Cancer. 2005;103(3):528–537. [DOI] [PubMed] [Google Scholar]
  • 89. Lindstrom S , Ma J , Altshuler D , et al. A large study of androgen receptor germline variants and their relation to sex hormone levels and prostate cancer risk. Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. J Clin Endocrinol Metab. 2010;95(9):E121–E127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90. Lapointe J , Li C , Giacomini CP , et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 2007;67(18):8504–8510. [DOI] [PubMed] [Google Scholar]
  • 91. Wang BD , Yang Q , Ceniccola K , et al. Androgen receptor-target genes in african american prostate cancer disparities. Prostate Cancer. 2013;2013:763569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92. Li Y , Hwang TH , Oseth LA , et al. AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate cancer progression. Oncogene. 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93. Mellinghoff IK , Vivanco I , Kwon A , Tran C , Wongvipat J , Sawyers CL. HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer Cell. 2004;6(5):517–527. [DOI] [PubMed] [Google Scholar]
  • 94. Craft N , Shostak Y , Carey M , Sawyers CL. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999;5(3):280–285. [DOI] [PubMed] [Google Scholar]
  • 95. Chan SC , Li Y , Dehm SM. Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal. J Biol Chem. 2012;287(23):19736–19749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. Hu R , Dunn TA , Wei S , et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69(1):16–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97. Mahajan NP , Liu Y , Majumder S , et al. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci USA. 2007;104(20):8438–8443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98. Shui IM , Mucci LA , Kraft P , et al. Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study. J Natl Cancer Inst. 2012;104(9):690–699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99. Signorello LB , Williams SM , Zheng W , et al. Blood vitamin d levels in relation to genetic estimation of African ancestry. Cancer Epidemiol Biomarkers Prev. 2010;19(9):2325–2331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100. Williams H , Powell IJ , Land SJ , et al. Vitamin D receptor gene polymorphisms and disease free survival after radical prostatectomy. Prostate. 2004;61(3):267–275. [DOI] [PubMed] [Google Scholar]
  • 101. Wang D , Zavadil J , Martin L , et al. Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis. Mol Cell Biol. 2011;31(17):3670–3680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102. Lescarbeau RM , Seib FP , Prewitz M , Werner C , Kaplan DL. In vitro model of metastasis to bone marrow mediates prostate cancer castration resistant growth through paracrine and extracellular matrix factors. PLoS One. 2012;7(8):e40372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103. Jia Z , Wang Y , Sawyers A , et al. Diagnosis of prostate cancer using differentially expressed genes in stroma. Cancer Res. 2011;71(7):2476–2487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104. Joesting MS , Perrin S , Elenbaas B , et al. Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer. Cancer Res. 2005;65(22):10423–10430. [DOI] [PubMed] [Google Scholar]
  • 105. Haiman CA , Chen GK , Blot WJ , et al. Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet. 2011;7(5):e1001387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106. Whittemore AS , Lele C , Friedman GD , Stamey T , Vogelman JH , Orentreich N. Prostate-specific antigen as predictor of prostate cancer in black men and white men. J Natl Cancer Inst. 1995;87(5):354–360. [DOI] [PubMed] [Google Scholar]
  • 107. Gokce N , Holbrook M , Duffy SJ , et al. Effects of race and hypertension on flow-mediated and nitroglycerin-mediated dilation of the brachial artery. Hypertension. 2001;38(6):1349–1354. [DOI] [PubMed] [Google Scholar]
  • 108. Amling CL , Riffenburgh RH , Sun L , et al. Pathologic variables and recurrence rates as related to obesity and race in men with prostate cancer undergoing radical prostatectomy. J Clin Oncol. 2004;22(3):439–445. [DOI] [PubMed] [Google Scholar]
  • 109. Hursting SD , Nunez NP , Varticovski L , Vinson C. The obesity-cancer link: lessons learned from a fatless mouse. Cancer Res. 2007;67(6):2391–2393. [DOI] [PubMed] [Google Scholar]
  • 110. Huang M , Narita S , Numakura K , et al. A high-fat diet enhances proliferation of prostate cancer cells and activates MCP-1/CCR2 signaling. Prostate. 2012;72(16):1779–1788. [DOI] [PubMed] [Google Scholar]
  • 111. Nguyen PL , Ma J , Chavarro JE , et al. Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival. J Clin Oncol. 2010;28(25):3958–3964. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular Endocrinology are provided here courtesy of The Endocrine Society

RESOURCES