Despite more aggressive screening across all demographics and gradual declines in mortality related to prostate cancer (PCa) in the United States, disparities among populations persist. A substantial proportion of African American men (AAM) have a higher overall incidence, earlier age of onset, increased proportion of clinically advanced disease, and increased bone metastases and mortality from PCa compared to European American men (EAM). Limited early evidence indicates that underlying causes for disparities may be observed in tumor-specific gene expression programs.
This study used microarray-based methods to measure expression levels for 517 genes that were previously associated with PCa in archived formalin-fixed paraffin embedded (FFPE) specimens; testing the hypothesis that gene expression features of functional consequence to cancer distinguish PCa from AAM and EAM. A t test was conducted comparing AAM to EAM expression levels for each probe on the array.
Analysis of 639 tumor samples (270 AAM, 369 EAM) showed that 95 genes were overexpressed specifically in PCa from AAM relative to EAM and 132 were overexpressed in PCa from EAM relative to AAM. Furthermore, systems-level analyses highlight the relevant signaling pathways and functions associated with the EAM- or AAM-specific overexpressed gene sets, for example, inflammation and lipid metabolism.
Results here bring further understanding to the potential for molecular differences for PCa in AAM versus EAM.
The results support the notion that therapeutic benefits will be realized when targeted treatments are designed to acknowledge and address a greater spectrum of PCa subtypes and molecular distinctions.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
The incidence of prostate cancer is approximately 60% higher and the mortality rate is 2 to 3 times greater in black than in white American men. We propose that a more rapid prostate cancer growth rate and/or earlier transformation from latent to aggressive prostate cancer in black than in white men contribute to this disparity.
Materials and Methods
We evaluated entirely embedded prostate glands on autopsy from 1,056 black and white men who died of causes other than prostate cancer. We also reviewed data from our radical prostatectomy database and from the Detroit Surveillance, Epidemiology and End Results database.
Autopsy data indicated that sub-clinical prostate cancer in black and white men starts at early age and clinical characteristics do not differ by race at early ages. Radical prostatectomy specimen data revealed that prostate cancer volume and Gleason grade were greater in black than in white men. Advanced or meta-static prostate cancer occurred at a 4:1 ratio in black and white men, respectively, in the Detroit Surveillance, Epidemiology and End Results registry database.
Results showed that age at prostate cancer initiation and clinical characteristics did not differ by race in our autopsy series, prostate cancer volume after radical prostatectomy was greater in black than in white men and disease became distant disease at a ratio of 4 black men to 1 white man in the Detroit Surveillance, Epidemiology and End Results population. These findings support the concept that prostate cancer grows more rapidly in black than in white men and/or earlier transformation from latent to aggressive prostate cancer occurs in black than in white men.
prostate; prostatic neoplasms; African continental ancestry group; European continental ancestry group; disease progression
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.
In humans, genetic variation and dietary factors may alter the biologic effects of exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the major heterocyclic amines generated from cooking meats at high temperatures that has carcinogenic potential through the formation of DNA adducts. Previously, we reported grilled red meat consumption associated with PhIP-DNA adduct levels in human prostate. In the present study, we expanded our investigation to estimate the associations between beverage consumption and PhIP-DNA adduct levels in prostate for 391 prostate cancer cases. Of the 15 beverages analyzed, red wine consumption had the strongest association with PhIP-DNA adduct levels showing an inverse correlation in both tumor (p=0.006) and non-tumor (p=0.002) prostate cells. Red wine consumption differed significantly between African-American and white cases, but PhIP-DNA adduct levels in prostate did not vary by race. In African Americans compared with whites, however, associations between red wine consumption and PhIP-DNA adduct levels were not as strong as associations with specific (e.g., SULT1A1 and UGT1A10 genotypes) and non-specific (e.g., African ancestry) genetic variation. In a multivariable model, the covariate for red wine consumption explained a comparable percentage (13-16%) of the variation in PhIP-DNA adduct levels in prostate across the two racial groups, but the aforementioned genetic factors explained 33% of the PhIP-DNA adduct variation in African-American cases, while only 19% of the PhIPDNA adduct variation in whites. We conclude that red wine consumption may counteract biologic effects of PhIP exposure in human prostate, but genetic factors may play an even larger role, particularly in African Americans.
compounds, heterocyclic; resveratrol; UDP-glucuronosyltransferase; sulfotransferases; African Americans; chemoprevention
Lung cancer continues to be the leading cause of cancer death in the USA and the best example of a cancer with undisputed evidence of environmental risk. However, a genetic contribution to lung cancer has also been demonstrated by studies of familial aggregation, family-based linkage, candidate gene studies and most recently genome-wide association studies (GWAS). The African-American population has been underrepresented in these genetic studies and has patterns of cigarette use and linkage disequilibrium that differ from patterns in other populations. Therefore, studies in African-Americans can provide complementary data to localize lung cancer susceptibility genes and explore smoking dependence-related genes. We used admixture mapping to further characterize genetic risk of lung cancer in a series of 837 African-American lung cancer cases and 975 African-American controls genotyped at 1344 ancestry informative single-nucleotide polymorphisms. Both case-only and case–control analyses were conducted using ADMIXMAP adjusted for age, sex, pack-years of smoking, family history of lung cancer, history of emphysema and study site. In case-only analyses, excess European ancestry was observed over a wide region on chromosome 1 with the largest excess seen at rs6587361 for non-small-cell lung cancer (NSCLC) (Z-score = −4.33; P = 1.5 × 10−5) and for women with NSCLC (Z-score = −4.82; P = 1.4 × 10−6). Excess African ancestry was also observed on chromosome 3q with a peak Z-score of 3.33 (P = 0.0009) at rs181696 among ever smokers with NSCLC. These results add to the findings from the GWAS in Caucasian populations and suggest novel regions of interest.
Recombination, together with mutation, is the ultimate source of genetic variation in populations. We leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing-over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P<10−245). We identify a 17 base pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of African-enriched alleles of PRDM9.
Metabolic syndrome refers to a set of conditions that increases the risk of cardiovascular disease and has been associated with an increased risk of prostate cancer, particularly among African American men. This study aimed to estimate the association of metabolic syndrome with biochemical recurrence (BCR) in a racially diverse population. Among 383 radical prostatectomy patients, 67 patients had documented biochemical recurrence. Hypertension was significantly, positively associated with the rate of BCR (hazard ratio (HR) = 2.1; 95% CI = 1.1, 3.8). There were distinct racial differences in the prevalence of individual metabolic syndrome components; however, the observed associations with BCR did not differ appreciably by race. We conclude that hypertension may contribute to a poorer prognosis in surgically treated prostate cancer patients. Our findings suggest that targeting components of the metabolic syndrome which are potentially modifiable through lifestyle interventions may be a viable strategy to reduce risk of BCR in prostate cancer.
Prostate cancer (PCa) is a complex disease that disproportionately affects African Americans and other individuals of African descent. A number of regions across the genome have been associated to PCa, most of them with moderate effects. A few studies have reported chromosomal changes on 12p and 12q that occur during the onset and development of PCa but to date no consistent association of the disease with chromosome 12 polymorphic variation has been identified. In order to unravel genetic risk factors that underlie PCa health disparities we investigated chromosome 12 using ancestry informative markers (AIMs), which allow us to distinguish genomic regions of European or West African origin, and tested them for association with PCa. Additional SNPs were genotyped in those areas where significant signals of association were detected. The strongest signal was discovered at the SNP rs12827748, located upstream of the PAWR gene, a tumor suppressor, which is amply expressed in the prostate. The most frequent allele in Europeans was the risk allele among African Americans. We also examined vitamin D related genes, VDR and CYP27B1, and found a significant association of PCa with the TaqI polymorphism (rs731236) in the former. Although our results warrant further investigation we have uncovered a genetic susceptibility factor for PCa in a likely candidate by means of an approach that takes advantage of the differential contribution of parental groups to an admixed population.
There are considerable racial disparities in prostate cancer risk, with a 60% higher incidence rate among African American (AA) men compared with European American (EA) men, and a 2.4 fold higher mortality rate in AA men than in EA men. Recently, studies have implicated several African-ancestry associated prostate cancer susceptibility loci on chromosome 8q24. In the current study, we performed admixture mapping in AA men from two independent case-control studies of prostate cancer to confirm the 8q24 ancestry association and also identify other genomic regions that may harbor prostate cancer susceptibility genes. A total of 482 cases and 261 controls were genotyped for 1,509 ancestry informative markers across the genome. The mean estimated individual admixture proportions were 20% European and 80% African. The most significant observed increase in European ancestry occurred at rs2141360 on chromosome 7q31 in both the case-only (p=0.0000035) and case-control analyses. The most significant observed increase in African ancestry across the genome occurred at a locus on chromosome 5q35 identified by SNPs rs7729084 (case-only analysis: p=0.002), and rs12474977 (case-control analysis: p=0.004), which are separated by 646 kb and were adjacent to one another on the panel. On chromosome 8, rs4367565 was associated with the greatest excess African ancestry in both the case-only and case-control analyses (case-only and case-control p=0.02), confirming previously reported African-ancestry associations with chromosome 8q24. In conclusion, we confirmed ancestry associations on 8q24, and identified additional ancestry-associated regions potentially harboring prostate cancer susceptibility loci.
Prostate Cancer; Admixture Mapping; Ancestry; PODXL; DOCK4
Metabolic syndrome refers to cluster of conditions serving as risk factors for cardiovascular disease. Metabolic syndrome is prevalent in the United States and the spectrum of specific features has been shown to differ by race and ethnicity. A number of recent reports link metabolic syndrome to prostate cancer, however most studies do not have racially diverse populations to explore differences in risk.
A case-control study was conducted to test the association between metabolic syndrome features and prostate cancer among 637 cases and 244 controls, with African Americans comprising 43% of the study population.
Metabolic syndrome, defined using a modified version of the ATP III criteria, was marginally associated with increased risk of prostate cancer in African Americans (OR=1.71; 95% CI=0.97, 3.01), but not Caucasians (OR=1.02; 95%CI=0.64, 1.62). After stratifying cases on stage at diagnosis, African American men with organ confined disease were more likely to have a history of metabolic syndrome compared to controls (OR=1.82; 95% CI=1.02, 3.23), but no association was observed among those with advanced stage disease (OR=0.93; 95%CI=0.31, 2.77). When evaluating specific features of metabolic syndrome, obesity was inversely related to prostate cancer among Caucasians (OR = 0.51, 95% CI=0.33, 0.80), but unrelated to risk among African Americans (OR=1.15; 95% CI=0.70, 1.89).
In this investigation, metabolic syndrome was associated with prostate cancer risk in African American men, but not Caucasians. The prevalence of this syndrome, coupled with the racial disparity and prostate cancer incidence and outcomes after diagnosis warrant further investigation.
insulin resistance; aggressive prostate cancer; African American; hypertension; diabetes; obesity
DNA adduct levels may be influenced by metabolic activity, DNA repair capabilities, and genomic integrity, all of which play a role in cancer progression.
To determine if elevated DNA adducts are a marker for prostate cancer progression, we measured polycyclic aromatic hydrocarbon - DNA adducts by immunohistochemistry in prostate cells of 368 surgical prostate cancer patients treated at the Henry Ford Hospital in Detroit, Michigan, between September 1999 and July 2004. Patients were followed up to 5 years after surgery with relative risk for biochemical recurrence (BCR) estimated with a Cox proportional hazards model that adjusted for standard clinical risk factors.
At 1 year of follow-up, patients with adduct levels above the median in tumor cells [hazard ratio (HR), 2.40; 95% confidence interval (95% CI), 1.10–5.27] and nontumor cells (HR, 3.22; 95% CI,1.40–7.39) had significant increased risk of BCR, but these HRs decreased to 1.12 (95% CI, 0.68–1.83) and 1.46 (95% CI, 0.89–2.41) in tumor and nontumor cells at 5 years postsurgery. When we restricted our analysis to patients with advanced-stage (III+) disease, those with high adduct levels in either tumor (53.5% versus 30.2%; P = 0.07) or nontumor (55.2% versus 28.6%; P = 0.02) cells had BCR rates almost 2-fold higher. In race-stratified analyses, the greatest risk of BCR associated with high adduct levels (in nontumor cells) was for African American patients younger than 60 years old (HR, 3.79; 95% CI,1.01–14.30).
High polycyclic aromatic hydrocarbon - DNA adduct levels in nontumor prostate cells are most strongly associated with BCR between 1 and 2 years after surgery and in patient subsets defined by younger age, advanced tumor stage, and African American race.
Men who carry the GSTP1 Val105 variant who are exposed at high levels to occupational PAH are at increased risk for prostate cancer. This increased risk is more pronounced in men under age 60 or with a family history of prostate cancer.
Variation in the glutathione S-transferase (GSTP1) gene and occupational polycyclic aromatic hydrocarbons (PAH) exposure are putative prostate cancer risk factors. An Ile/Val polymorphism in codon 105 of GSTP1 affects its enzymatic activity toward PAH detoxification, a possible mechanism in prostate carcinogenesis.
To determine whether the GSTP1 Ile105Val polymorphism modifies prostate cancer risk associated with occupational PAH exposure, we studied 637 prostate cancer cases and 244 controls of White and African-American race from the Henry Ford Health System in Detroit, Michigan. Occupational exposure to PAH from wood, petroleum, coal or other sources through respiratory and cutaneous routes was retrospectively assessed by expert review of job histories. The association of occupational PAH exposure and GSTP1 Ile105Val polymorphism with prostate cancer was tested in multiple logistic regression models adjusting for potential confounders. Cases were over sampled compared with controls to evaluate gene-environment interaction with the statistically efficient case-only analytic approach.
Neither carriage of the GSTP1 Val105 variant allele nor occupational PAH exposure was significantly associated with prostate cancer. However, case-only analyses revealed that carriage of the GSTP1 Val105 variant allele was associated with increasing levels of occupational respiratory PAH exposures from any source and from petroleum (trend test p-value = 0.01 for both). The GSTP1 Val105 allele was observed most frequently in cases in the highest quartile of occupational respiratory PAH exposures from petroleum (OR=1.74; 95% CI = 1.11–2.72) or from any source (OR=1.85; 95% CI = 1.19–2.89). The gene-environment risk estimate in the highest PAH petroleum exposure quartile was greatest in men under age 60 (OR=4.52; 95% CI = 1.96–10.41) or with a positive family history of prostate cancer (OR=3.02; 95% CI = 1.15–7.92).
Our results suggest men who carry the GSTP1 Val105 variant and are exposed at high levels to occupational PAH have increased risk for prostate cancer. This increased risk is more pronounced in men under age 60 or with a family history of prostate cancer.
glutathione S-transferase pi; case-control studies; DNA damage; logistic models
Polycyclic aromatic hydrocarbon (PAH)-DNA adducts may induce mutations that contribute to carcinogenesis. We evaluated potential associations between smoking and polymorphisms in PAH metabolism [CYP1A1 Ile462Val, CYP1B1 Ala119Ser and Leu432Val, microsomal epoxide hydrolase (mEH) Tyr113His and His139Arg, CYP3A4 A(−392)G] and conjugation [glutathione S-transferase (GST) M1 null deletion, GSTP1 Ile105Val] genes and PAH-DNA adduct levels (measured by immunohistochemistry) in tumor and nontumor prostate cells in 400 prostate cancer cases. Although no statistically significant associations were observed in the total sample, stratification by ethnicity revealed that Caucasian ever smokers compared with nonsmokers had higher adduct levels in tumor cells (mean staining intensity in absorbance units ± SE, 0.1748 ± 0.0052 versus 0.1507 ± 0.0070; P = 0.006), and Caucasians carrying two mEH 139Arg compared with two 139His alleles had lower adducts in tumor (0.1320 ± 0.0129 versus 0.1714 ± 0.0059; P = 0.006) and nontumor (0.1856 ± 0.0184 versus 0.2291 ± 0.0085; P = 0.03) cells. African Americans with two CYP1B1 432Val compared with two 432Ile alleles had lower adducts in tumor cells (0.1600 ± 0.0060 versus 0.1970 ± 0.0153; P = 0.03). After adjusting for smoking status, carrying the putative “high-risk” genotype combination, the faster metabolism of PAH-epoxides to PAH-diol-epoxides (CYP1B1 432Val/Val and mEH 139Arg/Arg) with lower PAH-diol-epoxide conjugation (GSTP1 105Ile/Ile), was associated with increased adducts only in Caucasian nontumor cells (0.2363 ± 0.0132 versus 0.1920 ± 0.0157; P = 0.05). We present evidence, for the first time in human prostate that the association between smoking and PAH-DNA adducts differs by race and is modified by common genetic variants.
Dihydrotestosterone (DHT) is believed to play an important role in prostate carcinogenesis. Five alpha reductase type II (SRD5A2) and 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2) are responsible for the biosynthesis and degradation of DHT in the prostate. Two polymorphisms, a valine (V) for leucine (L) substitution at the 89 codon of the SRD5A2 gene and a (TG)n,(TA)n,(CA)n repeat polymorphism within the third intron of the HSD3B2 gene were evaluated with regard to prostate cancer risk.
Blood samples were collected for 637 prostate cancer cases and 244 age and race frequency matched controls. In analysis, the SRD5A2 VL and LL genotypes were combined into one group and the HSD3B2 repeat polymorphism was dichotomized into short (<283) and long (≥283) alleles.
The SRD5A2 V89L polymorphism was not independently associated with prostate cancer risk. Carriage of at least one HSD3B2 intron 3 intron 3 short allele was associated with a significant increased risk for prostate cancer among all subjects (OR = 2.07, 95% CI =1.08–3.95, P = 0.03) and Caucasians (OR = 2.80, CI = 2.80–7.43, P = 0.04), but not in African Americans (OR = 1.50, CI =0.62–3.60, P =0.37). Stratified analyses revealed that most of the prostate cancer risk associated with the intron 3 HSD3B2 short allele was confined to the SRD5A2 89L variant subgroup and indicated that in combination these polymorphisms may be associated with increased risk of aggressive (Gleason >7) disease (Gleason >7).
In Caucasians, the HSD3B2 (TG)n,(TA)n,(CA)n intron 3 length polymorphism is associated with both prostate cancer risk and aggressiveness and the SRD5A2 V89L polymorphism may modify the risk conferred by this polymorphism.
SRD5A2 V89L; HSD3B2; prostate cancer; African American
African–American men have a higher dietary intake of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which is the most abundant heterocyclic amine in cooked meats and is carcinogenic in rat prostate through the formation of DNA adducts. To determine the clinical and demographic factors associated with PhIP-DNA adduct levels, the biologically effective dose of PhIP in human prostate, we immunohistochemically measured PhIP-DNA adducts in a study of 162 Caucasian and 102 African–American men who underwent radical prostatectomy for prostate cancer. A strong correlation between PhIP-DNA adduct levels in prostate tumor and adjacent non-tumor cells was observed (ρ = 0.62; p < 0.0001); however, non-tumor cells had significantly higher adduct levels compared with tumor (0.167 optical density (OD) units ± 0.043 vs. 0.104 OD ± 0.027; p < 0.0001). Race was not associated with PhIP-DNA adduct levels in either tumor or non-tumor cells, but race-specific associations were observed. In prostate tumor and non-tumor cells, tumor volume had the strongest association with PhIP-DNA adducts in Caucasians, whereas in African–Americans prostate volume was most strongly associated with adduct levels in tumor cells and advanced Gleason grade had the strongest association in non-tumor cells. In race interaction models, while the only statistically significant interaction was between African–American race and advanced Gleason grade in non-tumor cells (β = 0.029; p = 0.02), in tumor cells we observed opposite effects by race (positive for African–Americans, negative for Caucasians) for older age and high PSA levels at diagnosis. In conclusion, while PhIP-DNA adduct levels in prostate cells do not vary significantly by race, our results suggest that PhIP exposure may have stronger effects on prostate tumor differentiation in African–American men.
2-amino-1-methyl-6-phenylimidazo(45-b)pyridine; African–Americans; immunohistochemistry; neoplasms; DNA damage
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the major heterocyclic amine generated from cooking meats at high temperatures, and dietary exposures have been shown to induce prostate cancer in rats. PhIP derives its carcinogenic potential through the formation of PhIP-DNA adducts. The purpose of this study was to examine whether self-reported consumption and preparation doneness of grilled meats were associated with PhIP-DNA adduct levels in prostate epithelial cells. The study population consisted of 268 African-American and Caucasian men who underwent radical prostatectomy for prostate cancer. PhIP-DNA adducts in tumor and adjacent nontumor cells were measured using immunohistochemical methods, and dietary meat intake information was based on food frequency questionnaires. Data were analyzed using multivariate linear regression models. After adjusting for age at prostatectomy and race, grilled meat consumption (P = 0.002) was significantly associated with higher adduct levels in tumor cells, but this association seemed to be primarily due to consumption of grilled red meats (P = 0.001) as opposed to grilled white meat consumption (P = 0.15). Among the specific food items, grilled hamburger consumption had the most significant association with adduct level in tumor cells (P = 0.002). Similar trends in positive associations with grilled meat consumption and adduct levels were observed in nontumor cells, but none of these associations reached statistical significance. Our results suggest that dietary interventions targeted at lower consumption of grilled red meats may reduce prostate cancer risk via the PhIP prostate carcinogenic pathway.