UMLS:C0376358 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer incidence, clinical presentation, and mortality rates vary among different ethnic groups. A genetic variant of CYP3A4, a gene involved in the oxidative deactivation of testosterone, has been associated recently with prostate cancer development in Caucasians. To further investigate this variant, we evaluated its genotype frequencies in different ethnic groups and its association with clinical presentation of prostate cancer in African Americans. CYP3A4 genotypes were assayed in healthy male Caucasian (n = 117), Hispanic (n = 121), African-American (n = 116), Chinese (n = 46), and Japanese (n = 34) volunteers using the TaqMan assay. The association between CYP3A4 genotype and prostate cancer presentation was determined in 174 affected African-American men. Genotype frequency of the CYP3A4 variant differed substantially across ethnic groups, with African Americans much more likely to carry one or two copies than any other group (two-sided P < 0.0001). Among African Americans, 46% (80 of 174) of men with prostate cancer were homozygous for the CYP3A4 variant, whereas only 28% (32 of 116) of African-American healthy volunteers were homozygous (two-sided P < 0.005). A consistent positive association was observed between being homozygous for the CYP3A4 variant in African-American prostate cancer patients and clinical characteristics. Men homozygous for the CYP3A4 variant were more likely to present with higher grade and stage of prostate cancer in a recessive model [odds ratio (OR), 1.7; 95% confidence interval (CI), 0.9-3.4]. This association was even stronger for men who were >65 years of age at diagnosis (n = 103; OR, 2.4; 95% CI, 1.1-5.4). In summary, the CYP3A4 genotype frequency in different ethnic groups broadly followed trends in prostate cancer incidence, presentation, and mortality in the United States. African-American prostate cancer patients had a higher frequency of being homozygous for the CYP3A4 variant than healthy African-American volunteers who were matched solely based on ethnicity. Among the patients, those who were homozygous for the CYP3A4 variant were more likely to present with clinically more advanced prostate cancer.
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PMID:Association between a CYP3A4 genetic variant and clinical presentation in African-American prostate cancer patients. 1054 19

CYP3A4 is involved in the metabolism of numerous biologically active compounds, including testosterone. A genetic variant located in the P450NF (nifedipine) specific element (NFSE) has been identified that disrupts a transciptional regulatory element located in the 5' regulatory region of CYP3A4. The CYP3A4 variant (CYP3A4-V) is associated with the clinical presentation of prostate cancer. There are significant differences in CYP3A4 metabolism and rates of prostate cancer across ethnic groups that may be associated with CYP3A4 genotypes. Therefore, we estimated the frequency of the CYP3A4 variant in three ethnic groups with different prostate cancer incidence rates. The frequency (q) of CYP3A4-V was significantly different (p<0.0001) in African Americans (q=0.53), U.S. Caucasians (q=0.09), and Taiwanese (q=0.0). CYP3A4-V segregated in a Mendelian manner in one large African American family, and 7 of 16 (44%) biologically unrelated "marry-ins" carried a CYP3A4 variant allele. Reflecting population-specific prostate cancer incidence rates, our results suggest a high frequency of this variant in African Americans compared with U.S. Caucasians and Taiwanese.
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PMID:Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191. Online. 1066 Mar 43

A chemoprevention (CP) strategy has evolved for conducting efficient clinical trials for prostate cancer (PCa) prevention. It integrates five key components, including agents, biomarkers, cohorts, designs, and endpoints. The rationale for the CP strategy relates to the natural history of prostate cancer. There is a wide array of natural and synthetic agents that hold promise for inhibiting, reversing, or modulating the transition from normal to precancer and from precancer to cancer. These agent classes include antiandrogens, antiestrogens, phytoestrogens, antioxidants, anti-inflammatory (proapoptotic) agents, antiproliferation/antidifferentiation agents, signal transduction modulators of receptor tyrosine kinase and ras farnesylation, antiangiogenesis agents, insulinlike growth factor (IGF)-1, peroxisome proliferator-activator receptor modulators (-gamma and -delta), and gene-based interventions. Biomarkers and endpoints are guided by the level of evidence required (eg, phase 1, 2, 3). Two candidate surrogate endpoints (SE) based on histology are high-grade prostatic intraepithelial neoplasia (HGPIN) and computer-assisted image analysis of dysplastic lesions. Phase 1 trials use standard endpoints of safety, pharmacokinetics and limited pharmacodynamics. Phase 2 trials use endpoints of modulation of biomarkers and correlation with histology. Phase 3 trials use endpoints of clinical benefit, such as cancer incidence reduction and quality of life. Validation of a biomarker as a SE involves correlation of the biomarker with clinical benefit. Cohorts (target populations) for phase 2/3 trials include the general population of men over age 50 with a normal prostate-specific antigen (PSA), subjects with a strong family history of PCa, subjects with elevated PSA/negative biopsy, and subjects with HGPIN/negative biopsy. These at-risk populations reflect key individual risk factors (age, race, serum PSA [free/total]; serum IGF-1/IGF binding protein (IGFBP)-3; 1, 25(OH)(2) D3; family history of PCa; carriers of PCa susceptibility genes [ELAC2, CYP3A4, SRD5A2, etc.]; and histology such as atypia and HGPIN) that could be combined into a multivariate risk model for PCa. The probability of cancer risk (recurrence) is a key factor that impacts on the clinical trial design (power, sample size, and primary endpoint). Multivariate predictive mathematical models for biochemical recurrence after radical prostatectomy by decreasing sample size and time to clinical outcomes maximize trial efficiency and identify the patients most likely to benefit from secondary prevention. The two large primary prevention trials, Prostate Cancer Prevention Trial/Seleninium and Vitamin E Chemoprevention Trial (PCPT/ SELECT), in low- and average-risk subjects have sample sizes of 18,000 to 32,000, with a treatment duration of 7 years to detect a 25% reduction in biopsy-proven PCa. Subjects with HGPIN have the highest known cancer risk (approximately 50% at 3 years), and thus require a small sample size (n = 450) to detect a 33% reduction in cancer incidence. A schema involving three sequential trials for agent registration is described. In summary, a CP strategy that incorporates well-defined agents, clinical and validated SE, and high-risk cohorts defined by genetic and acquired risk factors in a series of well-designed randomized controlled trials provides an efficient pathway for evaluating and approving new agents for PCa prevention.
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PMID:Prostate cancer chemoprevention: Strategies for designing efficient clinical trials. 1129 33

Prostate cancer (PRCa) is one of the most common causes of cancer death in men and determinants of PRCa risk remain largely unidentified. Benign prostatic hyperplasia (BPH) is found in the majority of ageing men and has been linked with PRCa. CYP3A4 may influence PRCa through its role in testosterone metabolism. This nested case-control study assessed a CYP3A4 single nucleotide polymorphism as a risk factor for developing PRCa in patients with BPH. The CYP3A4 variant allele identified men with BPH who are at increased risk of progressing to PRCa (odds ratio 6.3, 95% CI 2.3-17.3), providing a potential tool to assist prediction strategies for this disease.
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PMID:CYP3A4 promoter variant is associated with prostate cancer risk in men with benign prostate hyperplasia. 1195 45

The human CYP3A subfamily plays a dominant role in the metabolic elimination of more drugs than any other biotransformation enzyme. CYP3A enzyme is localized in the liver and small intestine and thus contributes to first-pass and systemic metabolism. CYP3A expression varies as much as 40-fold in liver and small intestine donor tissues. CYP3A-dependent in vivo drug clearance appears to be unimodally distributed which suggests multi-genic or complex gene-environment causes of variability. Interindividual differences in enzyme expression may be due to several factors including: variable homeostatic control mechanisms, disease states that alter homeostasis, up- or down-regulation by environmental stimuli (such as smoking, drug intake, or diet), and genetic mutations. This review summarizes the current understanding and implications of genetic variation in the CYP3A enzymes. Unlike other human P450s (CYP2D6, CYP2C19) there is no evidence of a 'null' allele for CYP3A4. More than 30 SNPs (single nucleotide polymorphisms) have been identified in the CYP3A4 gene. Generally, variants in the coding regions of CYP3A4 occur at allele frequencies <5% and appear as heterozygous with the wild-type allele. These coding variants may contribute to but are not likely to be the major cause of inter-individual differences in CYP3A-dependent clearance, because of the low allele frequencies and limited alterations in enzyme expression or catalytic function. The most common variant, CYP3A4*1B, is an A-392G transition in the 5'-flanking region with an allele frequency ranging from 0% (Chinese and Japanese) to 45% (African-Americans). Studies have not linked CYP3A4*1B with alterations in CYP3A substrate metabolism. In contrast, there are several reports about its association with various disease states including prostate cancer, secondary leukemias, and early puberty. Linkage disequilibrium between CYP3A4*1B and another CYP3A allele (CYP3A5*1) may be the true cause of the clinical phenotype. CYP3A5 is polymorphically expressed in adults with readily detectable expression in about 10-20% in Caucasians, 33% in Japanese and 55% in African-Americans. The primary causal mutation for its polymorphic expression (CYP3A5*3) confers low CYP3A5 protein expression as a result of improper mRNA splicing and reduced translation of a functional protein. The CYP3A5*3 allele frequency varies from approximately 50% in African-Americans to 90% in Caucasians. Functionally, microsomes from a CYP3A5*3/*3 liver contain very low CYP3A5 protein and display on average reduced catalytic activity towards midazolam. Additional intronic or exonic mutations (CYP3A5*5, *6, and *7) may alter splicing and result in premature stop codons or exon deletion. Several CYP3A5 coding variants have been described, but occur at relatively low allelic frequencies and their functional significance has not been established. As CYP3A5 is the primary extrahepatic CYP3A isoform, its polymorphic expression may be implicated in disease risk and the metabolism of endogenous steroids or xenobiotics in these tissues (e.g., lung, kidney, prostate, breast, leukocytes). CYP3A7 is considered to be the major fetal liver CYP3A enzyme. Although hepatic CYP3A7 expression appears to be significantly down-regulated after birth, protein and mRNA have been detected in adults. Recently, increased CYP3A7 mRNA expression has been associated with the replacement of a 60-bp segment of the CYP3A7 promoter with a homologous segment in the CYP3A4 promoter (CYP3A7*1C allele). This mutational swap confers increased gene transcription due to an enhanced interaction between activated PXR:RXRalpha complex and its cognate response element (ER-6). The genetic basis for polymorphic expression of CYP3A5 and CYP3A7 has now been established. Moreover, the substrate specificity and product regioselectivity of these isoforms can differ from that of CYP3A4, such that the impact of CYP3A5 and CYP3A7 polymorphic expression on drug disposition will be drug dependent. In addition to genetic variation, other factors that may also affect CYher factors that may also affect CYP3A expression include: tissue-specific splicing (as reported for prostate CYP3A5), variable control of gene transcription by endogenous molecules (circulating hormones) and exogenous molecules (diet or environment), and genetic variations in proteins that may regulate constitutive and inducible CYP3A expression (nuclear hormone receptors). Thus, the complex regulatory pathways, environmentally susceptible milieu of the CYP3A enzymes, and as yet undetermined genetic haplotypes, may confound evaluation of the effect of individual CYP3A genetic variations on drug disposition, efficacy and safety.
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PMID:Genetic contribution to variable human CYP3A-mediated metabolism. 1240 45

Prostate cancer (PRCa) is one of the most common causes of cancer death in men and determinants of PRCa risk remain largely unidentified. Benign prostatic hyperplasia (BPH) is found in the majority of ageing men and has been associated with PRCa. Many candidate genes have been suggested to be involved in PRCa, such as those that are central to cellular growth and differentiation in the prostate gland. The vitamin D receptor (VDR) and CYP3A4 have been shown to be involved in the regulation of cell proliferation and differentiation in prostate cells. Genetic variations of these genes have been associated with PRCa in case-control studies and may be useful to detect BPH patients that have a higher risk of developing PRCa. The association between CYP3A4 and VDR TaqI SNPs and the risk of developing PRCa have been investigated in this study by determining the variant genotype frequencies of both SNPs in 400 patients with BPH who have been followed clinically for a median of 11 years. The results of this study showed that the incidence rate of PRCa was higher in BPH patients having CYP3A4 variant genotype compared to those with wild type (relative risk (RR)=2.7; 95% CI=0.77-7.66). No association between variant genotype and risk of developing PRCa was observed with the VDR TaqI variant genotype. In addition, the results of combined genotype analysis of these two SNPs showed a borderline significant association between CYP3A4 and VDR TaqI combined variant genotypes and PRCa risk (RR=3.43; 95% CI=0.99-11.77). While independent confirmation is required in further studies, these results provide a potential tool to assist prediction strategies for this important disease.
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PMID:CYP3A4 and VDR gene polymorphisms and the risk of prostate cancer in men with benign prostate hyperplasia. 1264 31

The increased incidence of prostate cancer, the most common cancer among men, has been attributed to aging and improved detection. Known risk factors include advanced age and African American ethnicity, but little is known about the causes of prostate cancer. Pathways involved in androgen metabolism, such as the CYP3A4-mediated steroid metabolism pathway, have been implicated in the etiology of prostate cancer. The CYP3A4 gene is associated with oxidative deactivation of testosterone. Studies suggest that the estimated frequency of this variant allele among healthy unrelated individuals is higher among African American men and that tumor stage and Gleason grade are increased in men with a mutation at the CYP3A4 gene site.
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PMID:CYP3A4: a potential prostate cancer risk factor for high-risk groups. 1269 Jun 15

Previous case-only studies have shown that men with the CYP3A4*1B promoter variant are at an increased risk of developing more aggressive forms of prostate cancer. However, no changes in CYP3A4 activity have been found in CYP3A4*1B carriers, suggesting that its association with disease may simply reflect linkage disequilibrium with another functional variant. CYP3A5 is located within 200 kb of CYP3A4, and a variant in CYP3A5 (*1/*3) correlates with function of the CYP3A5 enzyme. In this study, the potential effect of CYP3A4*1B and CYP3A5*1 on prostate cancer risk and aggressiveness were evaluated in a family-based case-control population. The CYP3A4*1B variant was positively associated with prostate cancer among Caucasians with more aggressive disease [odds ratio (OR), 1.91; 95% confidence interval (CI), 1.02-3.57; P=0.04], and inversely associated with risk among Caucasians with less aggressive disease (OR, 0.08; 95% CI, 0.01-0.49; P=0.006) and men with an age of diagnosis <63 (OR, 0.51; 95% CI, 0.26-1.00; P=0.05). The CYP3A5*1 variant was inversely associated with prostate cancer, especially among Caucasians with less aggressive disease (OR, 0.42; 95% CI, 0.22-0.78; P=0.006). As expected based on these genotype-level results, the CYP3A4*1B/CYP3A5*3 haplotype was positively associated with disease (OR, 2.91; 95% CI, 1.36-6.23; P=0.006), and the CYP3A4*1B/CYP3A5*1 haplotype was inversely associated with risk among Caucasians with less aggressive disease (OR, 0.07; 95% CI, 0.01-0.51; P=0.009). These findings suggest that the CYP3A4 and CYP3A5 variants, or other alleles on the haplotypes they help distinguish, are associated with prostate cancer risk and aggressiveness.
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PMID:CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate cancer. 1450 7

Genes involved in the testosterone biosynthetic pathway - such as CYP17A1, CYP3A4, and SRD5A2 - represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92-110 men from prostate cancer case-control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case-control sibships. Those SNPs exhibiting preliminary case-control allele frequency differences, or distinguishing (ie, 'tagging') common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case-control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case-control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P-values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P=0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer.
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PMID:Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2. 1456 Mar 15

We examined whether selected polymorphisms in 11 candidate genes and serum levels of insulin-like growth factor I (IGF-I) help predict the presence of prostate cancer among patients prescreened with prostate-specific antigen (PSA) and digital rectal exam (DRE). We studied 1031 consecutive men who underwent one or more prostate biopsies because of an elevated PSA level (>4 ng/ml) or an abnormal DRE. Eleven candidate genes were examined, including the androgen receptor, SRD5A2, CYP17, CYP3A4, vitamin D receptor, PSA, GST-T1, GST-M1, GST-P1, IGF-I, and IGF binding protein 3. We also measured serum IGF-I levels before biopsy. Of the 1031 men, 483 had cancer on any biopsy (cases) and 548 men had no cancer (controls). Age, ethnicity, total PSA, and DRE result were strongly predictive of the presence of prostate cancer. The mean IGF-I level for cases (119.4 ng/ml) was lower than for controls (124.4 ng/ml, P = 0.05) and were not predictive for the presence of prostate cancer. We found no associations between the androgen receptor, SRD5A2, CYP17, CYP3A4, vitamin D receptor, GST-M1, GST-P1, and IGF binding protein 3 genotypes and prostate cancer risk. The adjusted odds ratios for having prostate cancer for patients with the GST-T1 and IGF-I variant alleles were 1.64 (95% confidence interval, 1.1-2.4; P = 0.01) and 1.70 (95% confidence interval, 1.1-2.7; P = 0.02), respectively. Nine of 11 candidate genes were not significantly predictive for prostate cancer in a clinical setting. The GST-T1 and IGF-I polymorphisms demonstrated modest associations with prostate cancer risk. IGF-I levels were not helpful in identifying patients with prostate cancer at the time of biopsy.
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PMID:Comprehensive assessment of candidate genes and serological markers for the detection of prostate cancer. 1469 33

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