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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used data from a population-based cohort study of blacks, Hispanics, Japanese and whites to examine the frequency of prevalent prostate and breast cancer by family history status of first-degree relatives (parents and siblings). Independent of race, the age-adjusted relative risk for prevalent prostate cancer in subjects with affected brothers was approximately two times that in subjects with affected fathers (P < 0.00005). No such excess risk for breast cancer was observed among subjects with affected sisters compared to those with affected mothers (age- and race-adjusted relative risk = 1.10, P = 0.34). The magnitude of the relative risk for prostate cancer in sibling- versus parent-affected groups was significantly different from that of the comparable relative risk for breast cancer (P < 0.00005). An excess risk of prostate cancer in men with affected brothers compared to those with affected fathers is consistent with the hypothesis of an X-linked, or recessive, model of inheritance.
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PMID:Evidence of an X-linked or recessive genetic component to prostate cancer risk. 758 94

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. Complete or gross deletions of the androgen receptor gene have not been found frequently in persons with complete androgen insensitivity syndrome. Point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain, have been reported for partial and complete forms of androgen insensitivity. A relatively high number of mutations were reported in two different clusters in exon 5 and in exon 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain and which is encoded by the first half of exon 4. Androgen receptor gene mutations in prostate cancer are very rare and are reported only in exons 4-8. The X-linked spinal and bulbar muscle atrophy (SBMA; Kennedy's disease) is associated with an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
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PMID:Androgen receptor mutations. 762 93

The X-linked androgen receptor (AR) gene contains two polymorphic trinucleotide repeat segments that code for polyglutamine and polyglycine tracts in the N-terminal trans-activation domain of the AR protein. Changes in the lengths of these polymorphic repeat segments have been associated with increased risk of prostate cancer, an androgen-dependent tumor. Expansion of the polyglutamine tract causes a rare neuromuscular disease, spinal bulbar muscular atrophy, that is associated with low virilization, reduced sperm production, testicular atrophy, and infertility. As spermatogenesis is exquisitely androgen dependent, it is plausible that changes in these two repeat segments could have a role in some cases of male infertility associated with impaired spermatogenesis. To test this hypothesis, we examined the lengths of the polyglutamine and polyglycine repeats in 153 patients with defective sperm production and compared them to 72 normal controls of proven fertility. There was no significant association between the polyglycine tract and infertility. However, patients with 28 or more glutamines (Gln) in their AR had more than 4-fold (95% confidence interval, 4.9-3.2) increased risk of impaired spermatogenesis, and the more severe the spermatogenic defect, the higher the proportion of patients with a longer Gln repeat. Concordantly, the risk of defective spermatogenesis was halved when the polyglutamine tract was short (< or = 23 Gln). Whole cell transfection experiments using AR constructs harboring 15, 20, and 31 Gln repeats and a luciferase reporter gene with an androgen response element promoter confirmed an inverse relationship between Gln number and trans-regulatory activity. Immunoblot analyses indicated that the reduced androgenicity of the AR was unlikely to be due to a change in AR protein content. The data indicate a direct relation between length of the AR polyglutamine tract and the risk of defective spermatogenesis that is attributable to the decreased functional competence of AR with longer glutamine tracts.
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PMID:Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. 936 May 40

The incidence of prostate cancer (CaP) and its increase in the last 10 years vary both from country to country and according to the ethnic group, with the highest incidence reported for Afro-Americans and the lowest for Asian men. To date, only three risk factors have been established for CaP: age; familial aggregation of CaP, and ethnic origins. No dietary or environment-related cause has been established. However, some variations in endogenous genetic factors may help explain differences in risk among ethnic groups or geographic areas. Similarly, certain genetic polymorphisms of genes encoding for 5alpha-reductase, androgen receptor or vitamin D, have been associated with different levels of CaP risk, and could explain the variations observed between populations. Different studies support the view that familial CaP may truly be hereditary, and not due to a similar lifestyle. Thus, familial inheritance is a parameter that needs to be considered in recommending screening for high-risk families. Indeed, when 1, 2, and 3 first-degree relatives are affected, the relative risk of first-degree relatives of CaP patients may increase to 2, 5, and 11%, respectively. Some familial forms appear to be associated with transmission of a rare putative dominant gene with a high penetrance (88% at age 85), with the cumulative proportion of CaP attributable to this gene being more marked for younger patients (a 43 versus a 34% risk of CaP appearing before the age of 55 versus 70 years). Using this transmission model and linkage analysis, a predisposing locus on chromosome 1q24-25 (HPC-1) has been described. Moreover, recessive and X-linked transmission has been suggested, showing that a large proportion of familial CaP may not be due to segregation of a few major gene mutations, but rather to familial sharing of alleles at many loci, each contributing to a small increase in cancer risk. Candidate genes may be the same suppressor genes that are involved in other cancers and in sporadic CaP.
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PMID:Hereditary prostate cancer and other genetic predispositions to prostate cancer. 960 56

Whether androgen regulates the proliferation and survival of androgen-responsive prostate cancer cells directly or indirectly via a paracrine pathway initiated in androgen receptor (AR)-expressing stromal cells is unknown. To resolve this issue, female mice heterozygous for the testicular feminized male loss of function mutation in their X-linked AR genes were cross-bred to T cell-defective homozygous male nude mice. Using a PCR-based restriction enzyme digestion method, the resulting AR/tfm, Nu/nu F1 hybrid females were identified and back-crossed to homozygous male nude mice to produce AR-null male nude mice lacking both AR and T-cell function. Androgen-responsive PC-82 human prostate cancers were xenografted into these AR-null versus AR-wild-type male nude mice. In both backgrounds, the cancer cells did not grow in nonandrogenized hosts. In contrast, PC-82 prostate cancer cells grew with identical characteristics (i.e., take rate, morphology, PSA expression, growth rate, and percentage of cell proliferating or dying) in androgenized hosts of both backgrounds. Likewise, in both backgrounds, androgen ablation of mice bearing growing PC-82 cancers resulted in the inhibition of proliferation and activation of programmed (apoptotic) cell death of the cancer cells. These results demonstrate that both the androgen-stimulated proliferation and the suppression of programmed cell death of PC-82 human prostate cancer cells are initiated by the AR pathway directly within these cancer cells themselves and do not involve initiation by AR-expressing stromal cells in a paracrine manner.
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PMID:Development of an androgen receptor-null model for identifying the initiation site for androgen stimulation of proliferation and suppression of programmed (apoptotic) death of PC-82 human prostate cancer cells. 969 59

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.
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PMID:Evidence for a prostate cancer susceptibility locus on the X chromosome. 977 11

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found.
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PMID:Transcription map of Xq27: candidates for several X-linked diseases. 1019 60

Advanced hormone-independent prostate cancer is characterized by a significant loss of androgen receptor (AR) expression in 20-30% of the tumors. The transcriptional block underlying this phenomenon is not known, but we have proposed that methylation of CpG sites in the AR promoter may reversibly inactivate transcription of the AR (D. F. Jarrard et al, Cancer Res., 58: 5310-5314, 1998). In this study, detailed methylation analysis using bisulfite sequencing was performed on a series of AR expression-positive and -negative prostate cancer cells. We found that methylation of several consensus sequences in the AR promoter (from -131 to -121 and +44 to +54) are tightly linked to the loss of AR expression in metastatic hormone-independent prostate cancer cell lines. These consensus sites of methylation correlate with the minimal promoter region critical for AR transcription. In human tissues, no methylation was demonstrated in normal or primary prostate cancers that express the AR. Four of 15 tumors obtained from men who had died from hormone-independent prostate cancer demonstrated a significant loss of AR expression immunohistochemically and two (50%) of these AR-negative tumors contained AR methylation. We conclude that the AR promoter contains specific CpG methylation hot spots that are markers for gene silencing. Furthermore, AR methylation may represent a phenotype important in the development of hormone independence in a subset of advanced prostate cancer in which AR expression is lost. The finding of AR methylation also represents the first report of aberrant methylation on an X-linked gene associated with a somatic male cancer.
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PMID:Methylation of the androgen receptor minimal promoter silences transcription in human prostate cancer. 1091 77

Hyperandrogenism is currently thought to be central to the pathogenesis of polycystic ovarian syndrome (PCOS), a common endocrine disorder in premenopausal women characterized by irregular menstruation and anovulatory infertility. Although hyperandrogenism is characteristic, some women with PCOS have normal serum androgen levels. All androgens act through the X-linked androgen receptor (AR), the N-terminal domain of which contains a polyglutamine tract encoded by a highly polymorphic CAG trinucleotide repeat tract. Recently, variations in this CAG microsatellite tract, while remaining within the normal polymorphic range (11-38 CAGs), have been inversely correlated with receptor activity. Thus, short tracts are associated with high intrinsic AR activity and increased severity and earlier age of onset of the androgen-regulated tumor prostate cancer, whereas longer CAG tracts are associated with low AR activity and oligospermic infertility. To investigate the role of the CAG repeat tract in PCOS, we measured its length in 91 patients with ultrasound diagnosis of polycystic ovaries, irregular menstrual cycles, and anovulatory infertility and compared them to 112 control subjects of proven fertility with regular menses. Fluorescent-labeled DNA fragments containing the CAG repeat tract were amplified from leucocytic DNA, and their lengths were compared with internal size markers on an automated DNA Sequencer. There were no differences in the mean CAG length between patients and controls when both alleles were considered together or separately. Because there is a subset of PCOS patients whose serum androgens are normal, we compared differences in CAG length between patients whose serum testosterone (T) levels were below the normal laboratory mean, to those that were higher. There was a trend for a lower mean CAG biallelic length among anovulatory patients with T less than 1.73 nmol/L compared with those whose T was more than 1.73 nmol/L (22.47 +/- 0.36 vs. 23.25 +/- 0.29). This difference in CAG length between patients with low and high T levels (20.38 +/- 0.51 vs. 21.98 +/- 0.29) was highly significant (P = 0.004) when only the shorter allele of each individual was considered. Ethnic differences were also evident in our data; Indian subjects had a significantly shorter AR-CAG length compared with Chinese, being 22.08 +/- 0.50 and 23.16 +/- 0.17, respectively. Our data indicate an association between short CAG repeat length and the subset of anovulatory patients with low serum androgens, suggesting that the pathogenic mechanism of polycystic ovaries in these patients could be due to the increased intrinsic androgenic activity associated with short AR alleles.
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PMID:Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. 1099 52

There is a clear genetic component to prostate cancer susceptibility. Regions reported to be linked to prostate cancer include 1q24-25 (HPC-1), 1q42.2-43, and Xq27-28. There is limited genetic information on familial prostate tumors. We used the Utah Population Database to identify familial prostate cancer cases and selected 35 cases from high-risk families. Tissue blocks containing discernable tumor were available from 19 cases; 13 of these yielded adequate specimens for analysis. Six cases came from families with linkage to HPC-1, 3 were known to have linkage to Xq27-28, and 4 had no linkage to a known locus; 7 cases were analyzed from patients who showed no known linkage (sporadic tumors) as controls. These paraffin-embedded tumors were laser microdissected, degenerate oligonucleotide (DOP)-amplified, and labeled for fluorescence detection by comparative genomic hybridization (CGH). Loss of 7q, 10q, and 16q and gain of 8q were common abnormalities present in both familial and sporadic tumors. Distinctive abnormalities included loss of 3p12-3p22 in 3 of 6 HPC-7-linked cases and in 2 of 3 X-linked cases and gain of 6q11-6q21 in 2 each of HPC-1 and X-linked tumors. In conclusion, laser microdissection, DOP-PCR, and CGH is a feasible method for analysis of paraffin-embedded prostate tumors. This study provides preliminary data suggesting that familial prostate cancer harbors some unique genetic changes when compared with sporadic prostate tumors.
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PMID:Microdissection, DOP-PCR, and comparative genomic hybridization of paraffin-embedded familial prostate cancers. 1110 32


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