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)

Elevated dihydrotestosterone levels have been suggested to increase the risk of prostate cancer. The human SRD5A2 gene encodes the type II steroid 5 alpha-reductase, which converts testosterone to the more bioactive compound dihydrotestosterone. We have determined the distribution of a dinucleotide repeat in low-risk Asian-Americans, high-risk African-Americans, and intermediate-risk non-Hispanic Whites. We found this marker to be more polymorphic than previously reported, with some alleles being specific to African-Americans. Genetic variants of the SRD5A2 gene may play a role in predisposition to prostate cancer and in explaining the substantial racial/ethnic variability in risk.
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PMID:Genetic variability of the human SRD5A2 gene: implications for prostate cancer risk. 766 65

Prostate cancer is the most common serious cancer diagnosed in men in the United States. This disease is also characterized by a striking racial/ethnic variation in incidence: highest in African-Americans, intermediate in Caucasians, slightly lower in Latinos, and lowest in Asians. Ample biochemical and epidemiological evidence suggests a role for androgens, particularly testosterone and dihydrotestosterone, in prostate cancer etiology. We have analyzed a candidate gene for prostate cancer, SRD5A2, encoding prostatic steroid 5alpha-reductase type II, which converts testosterone into the more bioactive dihydrotestosterone, for mutations. We report here one amino acid substitution, V89L, which replaces valine at codon 89 with leucine. This substitution is a "germline" (constitutional) DNA polymorphism, and it is common, panethnic, and reduces in vivo steroid 5alpha-reductase activity. This substitution is particularly common among Asians and may explain the low risk for prostate cancer in this population.
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PMID:A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. 906 62

Prostate cancer is a serious public health problem in many industrialized countries. Androgens appear to play a critical role in its etiology. Specifically, the active androgen in the prostate, dihydrotestosterone (DHT) which is synthesized by the enzyme steroid 5alpha-reductase from testosterone (T), acts as a mitogen. Hence androgen-deprivation is commonly used during prostate cancer therapy. Two isozymes for steroid 5alpha-reductase have been reported. The type II enzyme is prostate-specific and encoded by the SRD5A2 gene. We have investigated a polymorphic (TA)n dinucleotide repeat in the 3' UTR (untranslated region) of the SRD5A2 gene in 30 matched samples of constitutional ("germline") DNA from peripheral blood lymphocytes and microdissected, pure tumor DNA. We report here 8 LOH (loss of heterozygosity) events and 9 cases of microsatellite instability at this marker. Therefore, almost 57% of the samples examined showed evidence of somatic mutations at the 3' UTR of the SRD5A2 locus. Our data suggest that the SRD5A2 gene may be involved in prostate cancer progression and that this may have relevance for treatment of the disease.
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PMID:Somatic mutations at the SRD5A2 locus encoding prostatic steroid 5alpha-reductase during prostate cancer progression. 1008 7

The prostate is an androgen-regulated organ, which has led to longstanding interest in the role of androgens in prostate carcinogenesis. Although evidence of a hormonal etiology for prostate cancer is strong, it is almost entirely circumstantial. Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-specific exposure to endogenous steroid hormones. The international and racial-ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, have suggested that genetic factors play a central role in determining prostate cancer risk. We are developing a polygenic model of prostate carcinogenesis, focused around a series of genes involved in androgen biosynthesis, transport and metabolism. We have begun to develop this model by utilizing sequence variants to study how polymorphic markers in two genes (SRD5A2 and AR) are related to prostate cancer risk within and between racial-ethnic groups. We are now collaborating with the Whitehead Institute/MIT, Center for Genome Research, to screen for single nucleotide polymorphisms in additional genes relevant to the androgen pathway and prostate cell growth. The model when fully developed can potentially provide a basis for targeting populations for screening interventions and for implementing primary preventive strategies.
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PMID:Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. 1032 89

Prostate cancer will be diagnosed in about 179,300 men in the US in 1999 alone. Some 37,000 individuals die of this disease annually. Prostate cancer is characterized by a substantial racial/ethnic variation in risk: highest in African-American men, lowest in Asian men and intermediate in Caucasian and Latino men. We set out to investigate as our central hypothesis that genetic variants of genes involved in androgen metabolism by themselves and in combination significantly contribute to prostate cancer progression and its racial/ethnic variation. Specifically, we examined the hypothesis that DNA sequence (allelic) variations in the type II (or prostatic) steroid 5alpha-reductase (SRD5A2) gene contribute substantially to the risk and progression of prostate cancer particularly across racial/ethnic lines. The "candidate gene", SRD5A2, was chosen because the reaction product [i.e. dihydrotestosterone (DHT)] of the enzyme encoded by this gene modulates directly cell division in the prostate. DHT binds to the androgen receptor (AR) and the DHT-AR complex leads to the transactivation of a variety of genes which ultimately modulates cell division in the prostate. Epidemiologic evidence suggests that variation in DHT levels play an important role in risk of prostate cancer. Thus, steroid 5alpha-reductase activity encoded by SRD5A2 variant alleles may be important in regulating intraprostatic DHT steady state levels by controlling its biosynthesis. A second candidate gene, the type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) gene, encodes the enzyme that initiates the metabolic inactivation of testosterone (T) to DHT. We have identified allelic variants in this gene as well. Here I review our strategy for identifying candidate genes for prostate cancer, a multifactorial disease. I summarize the significant findings, particularly of allelic variants in the HSD3B2 and SRD5A2 genes and discuss how they by themselves, in combination and through interactions with the environment may play a role in prostate cancer predisposition and its progression. Our approach, a multidisciplinary genomic genetic (GEN GEN) attack on the problem, may be useful in the analysis of other complex phenotypes as well.
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PMID:GEN GEN: the genomic genetic analysis of androgen-metabolic genes and prostate cancer as a paradigm for the dissection of complex phenotypes. 1041 59

Prostate cancer is the most common malignancy in males and is the second most common cause of cancer mortality in American men. Polymorphisms have been identified in two genes, the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5-reductase type II gene (SRD5A2) that are involved with androgen biosynthesis and metabolism. The CYP17 A2 allele contains a T-->C transition in the 5' promoter region that creates an additional Sp1-type (CCACC box) promoter site. The SRD5A2 valine to leucine (V89L) polymorphism has been correlated with lower dihydroxytestosterone levels. We tested genotypes in 108 prostate cases and 167 controls along with samples (n = 340) from several different ethnic groups. The CYP17 A2 allele (combined A1/A2 and A2/A2 genotypes) occurred at a higher frequency in Caucasian patients with prostate cancer (70%) than in Caucasian clinical control urology patients (57%), suggesting that the A2 allele may convey increased risk for prostate cancer [odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.0-3.0]. Blacks and Caucasians had a similar frequency of the A2 genotype (16 and 17%, respectively) while Taiwanese had the highest frequency (27%). The SRD5A2 leucine genotype was most frequent in Taiwanese (28%), intermediate in Caucasians (8.5%) and lowest in Blacks (2.5%). Genotypes having a SRD5A2 leucine allele were somewhat more common in prostate cancer cases (56%) than in controls (49%) (OR = 1.4, 95% CI = 0.8-2.2) but this difference was not significant. These results support the hypothesis that some allelic variants of genes involved in androgen biosynthesis and metabolism may be associated with prostate cancer risk.
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PMID:Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2). 1046 17

5alpha-Reductase type 2, the predominant prostatic isozyme of this protein, converts testosterone to dihydrotestosterone. It has been hypothesized that individuals with greater 5alpha-reductase activity are at increased risk for prostate cancer (CaP). A single nucleotide polymorphism of the 5alpha-reductase type 2 gene (SRD5A2) gives rise to a substitution of leucine (leu) for valine (val) at codon 89 (V89L), the presence of which may affect serum androstanediol glucuronide (AAG) levels. We studied the effect of this polymorphism on the risk of prostate cancer in a prospective, nested, case-control design within the Physicians' Health Study. In all controls (n = 799), the leu allele frequency was 0.30. Among the 386 controls with plasma AAG levels available, there was no significant association between AAG levels and V89L genotype. We also detected no significant association between risk for CaP and genotype [odds ratio: val/val = 1.0 (reference), leu/val = 0.96 (95% confidence interval, 0.76-1.20), and leu/ leu = 0.84 (95% confidence interval, 0.57-1.24)]. These data do not support a moderate to large effect of the SRD5A2 V89L polymorphism on plasma AAG levels or CaP risk in this predominantly Caucasian cohort, although a small effect cannot be completely excluded.
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PMID:The V89L polymorphism in the 5alpha-reductase type 2 gene and risk of prostate cancer. 1060 27

Hormone-related cancers, namely breast, endometrium, ovary, prostate, testis, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis. Endogenous and exogenous hormones drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors. The emergence of a malignant phenotype depends on a series of somatic mutations that occur during cell division, but the specific genes involved in progression of hormone-related cancers are currently unknown. In this review, the epidemiology of endometrial cancer and breast cancer are used to illustrate the paradigms of hormonal carcinogenesis. Then, new strategies for early detection and prevention of hormonal carcinogenesis are discussed. This includes developing polygenic models of cancer predisposition and the further development of safe and effective chemopreventives that block target sequence activity. We developed polygenic models for breast and prostate cancer after hypothesizing that functionally relevant sequence variants in genes involved in steroid hormone metabolism and transport would act together, and also interact with well-known hormonally related risk factors, to define a high-risk profile for cancer. A combination of genes each with minor variation in expressed activity could provide a degree of separation of risk that would be clinically useful as they could yield a large cumulative difference after several decades. The genes included in the breast cancer model are the 17beta-hydroxysteroid dehydrogenase 1 (HSD17B1) gene, the cytochrome P459c17alpha (CYP17) gene, the aromatase (CYP19) gene, and the estrogen receptor alpha (ER) gene. The prostate cancer model includes the androgen receptor gene (AR), steroid 5alpha-reductase type II (SRD5A2), CYP17 and the 3beta hydroxysteroid dehydrogenase (HSD3B2) gene. We present data from our multi-ethnic cohort to support these models.
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PMID:Hormonal carcinogenesis. 1123 97

The enzyme product of SRD5A2, 5alpha-reductase type II, is responsible for converting testosterone to the more metabolically active dihydrotestosterone. Therefore, SRDSA2 may be involved in the development or growth of prostate tumors. To examine the effects of allelic variants in the gene SRDSA2 on the presentation of prostate tumors, we studied a sample, primarily Caucasian, of 265 men with incident prostate cancer who were treated by radical prostatectomy. We assessed the relationship of the A49T and V89L polymorphisms at SRD5A2 with clinical and pathological tumor characteristics of these patients. We found no association of V89L genotypes with any of the characteristics studied. The presence of the A49T variant was associated with a greater frequency of extracapsular disease [odds ratio (OR), 3.16; 95% confidence interval (CI), 1.03-9.68] and a higher pathological tumor-lymph node-metastasis (pTNM) stage (OR, 3.11; 95% CI, 1.01-9.65). In addition, the A49T variant was overrepresented in two poor prognostic groups, which have been correlated with reduced rates of biochemical disease-free survival. One group included men with at least two of the following poor prognostic variables: (a) stage T3 tumor; (b) PSA level >10; and/or (c) Gleason score, 7-10 (OR, 3.46; 95% CI, 1.04-11.49). The second group included men with positive margins and high Gleason score (OR, 6.28; 95% CI, 1.05-37.73). Our results suggest that the A49T mutation may influence the pathological characteristics of prostate cancers and, thus, may affect the prognosis of these patients.
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PMID:Association of SRD5A2 genotype and pathological characteristics of prostate tumors. 1074 32

Human prostatic steroid 5alpha-reductase, encoded by the SRD5A2 gene on chromosome band 2p23, catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH as its cofactor. This enzyme has never been purified but a number of competitive inhibitors have been developed for this enzyme since increased steroid 5alpha-reductase activity may cause benign prostatic hypertrophy and prostate cancer. We report here the detailed biochemical and pharmacogenetic dissection of the human enzyme by analysing 10 missense substitutions and three double mutants which are all naturally found in humans. Nine of these 13 mutants reduce activity (measured as Vmax) by 20% or more, three increase steroid 5alpha-reductase by more than 15% and one results in essentially unaltered kinetic properties suggesting that it is a truly neutral ('polymorphic') amino acid substitution. Substantial pharmacogenetic variation among the mutants was also observed when three competitive inhibitors, finasteride, GG745 (dutasteride) and PNU157706, were investigated. Our studies not only define the substrate and cofactor binding sites of human steroid 5alpha-reductase, but also have significant consequences for the pharmacological usage of steroid 5alpha-reductase inhibitors in human patients treated for prostatic conditions.
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PMID:Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. 1089 10


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