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)

Previous studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are <2.0, much larger sample sizes will be required for confirmation.
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PMID:Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer. 1750 24

We examined the combined effect of circulating sex hormones and SRD5A2 V89L polymorphism on prostate cancer risk in a case-control study (300 cases and 300 controls) nested within the Carotene and Retinol Efficacy Trial. A moderate increase in risk associated with above-median serum levels of androstenedione and dehydroepiandrosterone sulfate (DHEAS) was present irrespective of V89L genotype. However, in L/L or V/L men, above-median DHEAS levels were associated with an increased risk of aggressive tumors [odds ratios (OR), 3.12; 95% confidence interval (95% CI), 1.28-7.63] but not of nonaggressive ones (OR, 0.56; 95% CI, 0.25-1.25). Above-median serum levels of free estradiol were associated with a lower risk, especially for aggressive cancer. The association with aggressive disease was more pronounced in men with a V/V genotype (OR, 0.34; 95% CI, 0.14-0.81), than in men with an L/L or V/L genotype (OR, 0.77; 95% CI, 0.37-1.60). Above-median levels of 3alpha-diol G were associated with an increased risk, but only in men with the L/L or V/L genotype (OR, 2.16; 95% CI, 1.31-3.56). The increase in risk in L/L and V/L men was restricted to aggressive tumors. Our study observed that only in men with the L/L or V/L genotype were increased serum levels of DHEAS and 3alpha-diol G positively associated with a higher risk of aggressive prostate cancer. Free estradiol levels were negatively associated with risk of aggressive prostate cancer in men with the V/V genotype. However, the absence of an overall association between V89L genotype and aggressive prostate cancer argues for a cautious interpretation of these observations.
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PMID:V89L polymorphism of the 5alpha-reductase Type II gene (SRD5A2), endogenous sex hormones, and prostate cancer risk. 1826 11

Prostate cancer is a leading solid tumor among men in the Western world. Androgens play an important role in the carcinogenesis and treatment of prostate cancer. CYP3A5 is a cytochrome P450 superfamily member which also has activity in testosterone metabolism. In this study, we looked for two-gene interactions associated with clinical characteristics of prostate cancer in the Finnish population. We used multifactor-dimensionality reduction for the identification of the two-gene interactions in androgen metabolism pathway genes together with clinical characteristics of prostate cancer among 754 genotyped prostate cancer patients. The CYP3A5*3/*3 and SRD5A2 A49T GG genotype interaction was associated with the clinical tumor stage T2-T4 (T-stage, TNM classification) with odds ratio (OR) 2.14, 95% confidence interval (CI) 1.35-3.40. Patients with CYP3A5*3/*3 and KLK3 I179T CC/TC genotypes had increased OR 2.30, 95% CI 1.16-4.58 for metastatic disease. Further, two-gene interaction CYP3A5*3/*3 and KLK3 -252A > G AA was associated with Gleason scores >or=7 with OR 1.52, 95% CI 1.11-2.09. Prostate cancer patients with CYP3A5*3/*3 and KLK -252A > G GG/AG genotypes had decreased OR of 0.70 with 95% CI 0.50-0.98 for high prostate-specific antigen levels at diagnosis. For prostate cancer patients aged below 65 years, the OR for interaction of CYP3A5*1/*3 or *1/*1 and AKR1C3 Q5H CC genotypes was 1.84 with 95% CI 1.03-3.28. For prostate cancer, the best two-gene interaction included genotypes SRD5A2 V89L GG and AKR1C3 Q5H CC with OR 1.30, 95% CI 1.01-1.66. It remains to be clarified whether these polymorphism associations identified here are also present in other populations.
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PMID:The interaction of CYP3A5 polymorphisms along the androgen metabolism pathway in prostate cancer. 1830 54

The steroid 5-alpha reductase type II gene (SRD5A2) encodes the enzyme which converts testosterone (T) to the more active androgen dihydrotestosterone. A non-synonymous single-nucleotide polymorphism, A49T (rs9282858), in SRD5A2 has been implicated in prostate cancer risk; however, results have been inconsistent. In 1999, we reported a strong association between the A49T variant and prostate cancer risk among African-Americans and Latinos in the Hawaii-Los Angeles Multiethnic Cohort (MEC). We report here an updated analysis of MEC data including the five major ethnic groups of the MEC, an increased sample size, improved genotyping technology and a comprehensive meta-analysis of the published literature. We found a non-statistically significant positive association between prostate cancer risk and carrying either the AT or TT genotype [odds ratio (OR) = 1.16, 95% confidence interval (CI) 0.79-1.69] in the MEC. This finding is in contrast to our previous results of ORs of 3.28 and 2.50 for the association between prostate cancer risk and the variant in African-American and Latino men, respectively; this can be accounted for by genotyping error in our earlier study. Meta-analysis of the published literature, including the current MEC data, shows a summary OR of 1.13 (95% CI 0.95-1.34) for the A49T variant with prostate cancer risk among sporadic, unselected cases. After evaluating more than 6000 cases and 6000 controls, there is little evidence of a role for the SRD5A2 A49T variant in prostate cancer risk. Overall, this report highlights the importance of rigorous genotyping quality control measures and replication efforts in genetic association studies.
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PMID:No association between the SRD5A2 gene A49T missense variant and prostate cancer risk: lessons learned. 1846 42

The age-adjusted risk of prostate cancer (PC) has increased in Singapore since 1968. We investigated the relationship between polymorphisms in four genes, androgen receptor (AR), prostate-specific antigen (PSA), 5alpha-reductase type II (SRD5A2) and cytochrome P450c17alpha (CYP17) and PC and benign prostatic hyperplasia (BPH). Men with shorter CAG repeats in AR and above 69 years at diagnosis showed a trend of decreased PC risk (OR=0.28, 95% CI=0.08-1.03; p=0.05). Shorter CAG repeats and non-GG genotypes in the AR and PSA loci, respectively, showed a trend of decreased PC risk (OR=0.25, 95% CI=0.06-1.03; p=0.06) and a significantly decreased BPH risk (OR=0.38, 95% CI=0.15-0.94; p=0.04). The results indicate that allelic variation in PSA promoter activity may be androgen dependent and interaction of genes in androgen pathway may influence the risk of BPH and PC in Singapore males.
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PMID:Shorter CAG repeats in androgen receptor and non-GG genotypes in prostate-specific antigen loci are associated with decreased risk of benign prostatic hyperplasia and prostate cancer. 1849 32

Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
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PMID:Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. 1851 8

Multiple pathways of prostate carcinogenesis have been proposed, including those involving androgen metabolism and inflammation. These pathways are not independent, and may act together in prostate cancer etiology: androgens promote both inflammatory processes and serve as mitogens in prostate tumor growth. To explore the possible joint effects of these pathways in prostate cancer severity, we studied 1,090 Caucasian prostate cancer cases to evaluate whether tumor severity is influenced by a history of benign prostatic hyperplasia (BPH) interacting with genotypes involved in inflammation or androgen metabolism including MSR1, RNASEL, AR, CYP3A4, CYP3A43, CYP3A5 and SRD5A2. We observed a statistically significant interaction between a number of genotypes and BPH. After considering the potential for false positive associations, the only remaining significant associations involved CYP3A43 P340A genotypes and history of BPH on both Gleason grade (interaction p-value = 0.026) and tumor stage (interaction p-value = 0.017). These results suggest that androgen metabolism may act in concert with inflammatory phenotypes such as BPH in determining prostate cancer severity.
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PMID:Joint effects of inflammation and androgen metabolism on prostate cancer severity. 1856 91

Somatic mutations are hallmarks of cancer progression. We sequenced 26 matched human prostate tumor and constitutional DNA samples for somatic alterations in the SRD5A2, HPRT, and HSD3B2 genes, and identified 71 nucleotide substitutions. Of these substitutions, 79% (56/71) occur within a WKVnRRRnVWK sequence (a novel motif we call THEMIS [from the ancient Greek goddess of prophecy]: W=A/T, K=G/T, V=G/A/C, R=purine (A/G), and n=any nucleotide), with one mismatch allowed. Literature searches identified this motif with one mismatch allowed in 66% (37/56) of the somatic prostate cancer mutations and in 74% (90/122) of the somatic breast cancer mutations found in all human genes analyzed. We also found the THEMIS motif with one allowed mismatch in 88% (23/26) of the ras1 gene somatic mutations formed in the sensitive to skin carcinogenesis (SENCAR) mouse model, after induction of error-prone DNA repair following mutagenic treatment. The high prevalence of the motif in each of the above mentioned cases cannot be explained by chance (P<0.046). We further identified 27 somatic mutations in the error-prone DNA polymerase genes pol eta, pol kappa, and pol beta in these prostate cancer patients. The data suggest that most somatic nucleotide substitutions in human cancer may occur in sites that conform to the THEMIS motif. These mutations may be caused by "mutator" mutations in error-prone DNA polymerase genes.
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PMID:Genomic analysis of cancer tissue reveals that somatic mutations commonly occur in a specific motif. 1862 41

Prostate cancer represents a heterogeneous disease with varying degrees of aggressiveness, patterns of metastasis, and response to therapy. It arises from a complex etiology that involves both exogenous (diet, environment, etc.) and endogenous (hormonal and genetic) factors. The present study was performed to explore the role of various genotypes involved in steroid metabolism and synthesis in the causation of prostate cancer. Genetic polymorphism of the ER, CYP17, SRD5A2 (TA repeats), and PSA genes were analyzed in 157 cases of prostate cancer and 340 controls [170 healthy males and 170 patients of benign prostate hyperplasia (BPH)]. Mutant genotypes of ER and CYP17 showed 2- and 3- and 3.5-fold increased risk of prostate cancer, respectively, as compared to BPH and healthy controls. Interaction of mutant (homozygous and heterozygous) alleles of CYP17 with TA (0/0) led to a twofold increased risk of prostate cancer. Risk was more than twofold with the combination of mutant alleles of ER and CYP17. The PSA gene polymorphism did not show any increased risk of prostate cancer. This indicates the role of mutant allele of ER and CYP17 in the development and progression of prostate cancer and rules out any increased risk with PSA polymorphism in the north Indian population.
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PMID:Role of hormonal genes and risk of prostate cancer: gene-gene interactions in a North Indian population. 1872 76

Androgens are essential to normal prostate growth and development. It is therefore possible that polymorphisms in the androgen synthesis gene 5alpha-reductase type II (SRD5A2) may be involved in the progression of prostate tumors. We evaluated the relationship of two single-nucleotide polymorphisms, A49T and V89L, with prostate cancer risk in a case-control study. A total of 114 prostate cancer patients and 144 healthy control males were genotyped. We found highly significant differences between the two polymorphisms, the risk of developing prostate cancer, and some of the clinical-pathologic characteristics. Individuals who carry at least one V allele may have a higher risk of developing prostate cancer [odds ratio (OR) = 7.5, 95% confidence interval (CI) = 2.57-22.08, P<0.001]. In addition, individuals with LL genotype showed reduction in the progression to a higher tumor stage (OR = 0.10, 95%CI = 0.040-0.27, P<0.001). The A49T substitution was associated with a higher pTNM stage (OR = 2.87, 95%CI 1.14-7.21, P = 0.003) and elevated Gleason grade (OR = 3.14, 95%CI = 1.12-8.78; P = 0.004). Furthermore, the allelic frequencies of the A49T variant (33% controls and 45% cases) are the highest reported worldwide. These findings suggest that among the Ecuadorian population, these polymorphisms influence the risk of developing prostate cancer.
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PMID:Association among polymorphisms in the steroid 5alpha-reductase type II (SRD5A2) gene, prostate cancer risk, and pathologic characteristics of prostate tumors in an Ecuadorian population. 1921 86


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