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)

Recent research implicates viral infection as a factor that may contribute to the risk of prostate cancer. Allelic variation at the RNASEL locus is associated with the risk of infection by a newly discovered retrovirus called XMRV, and with hereditary risk of prostate cancer. This evidence suggests that the RNASEL locus has undergone antagonistic coevolution with the retrovirus over evolutionary time. If this is the case, then both the RNASEL locus and the retrovirus should show evidence of positive selection. Here we use molecular-evolutionary methods to investigate the prediction that the RNASEL locus will exhibit evidence of positive selection. We find evidence that positive selection has acted on this locus over evolutionary time. We further find, using a Bayesian estimation procedure, that Asp541Glu, which was found to be associated with prostate cancer risk in Caucasians in a recent meta-analysis, shows an elevated probability of positive selection. Previous studies provide evidence for rapid evolution of the infection-mediating gag gene in the XMRV retrovirus. Taken together, these results suggest that antagonistic coevolution may have occurred between a specific host locus involved in immune defense (RNASEL) and a viral pathogen. In turn, genetic variation associated with this apparent coevolution may influence susceptibility to prostate cancer.
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PMID:Molecular evolution of the prostate cancer susceptibility locus RNASEL: evidence for positive selection. 1829 51

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

The present review comes from the authors of the recent Scientific Advisory Committee on Nutrition (SACN) review Update on Trans Fatty Acids and Health, and focuses on assessing the strength of the evidence for a link between trans-fatty acid (trans-FA) intake and cancer. It evaluates a range of human ecological, case-control and prospective studies with trans-FA exposure assessed using either dietary assessment methods or trans-FA levels in tissues. Relevant animal studies are also presented in order to elucidate potential mechanisms. It concludes that there is weak and inconsistent evidence for a relationship between trans-FA and breast or colorectal cancer. Evidence for an association between trans-FA and prostate cancer is limited, but a recent large case-control study has shown a strong interaction between risk and trans-FA intake for the RNASEL QQ/RQ genotype that is present in about 35 % of the population. This potential association requires further investigation. The single study on non-Hodgkin's lymphoma reported a strong positive association, but only used a single assessment of dietary trans-FA made at the start of the study in 1980, and the significant changes in trans-FA intakes between then and the end of follow-up in 1994 limit the reliability of this observation. There is insufficient evidence to allow any differentiation between the effects of trans-FA from animal or vegetable origin on cancer risk.
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PMID:Trans-fatty acids and cancer: the evidence reviewed. 1908 70

The genetic variants underlying the strong heritable component of prostate cancer remain largely unknown. Genome-wide association studies of prostate cancer have yielded several variants that have significantly replicated across studies, predominantly in cases unselected for family history of prostate cancer. Additional candidate gene variants have also been proposed, many evaluated within familial prostate cancer study populations. Such variants hold great potential value for risk stratification, particularly for early-onset or aggressive prostate cancer, given the comorbidities associated with current therapies. Here, we investigate a Caucasian study population of 523 independent familial prostate cancer cases and 523 age-matched controls without a personal or family history of prostate cancer. We replicate identified associations at genome-wide association study loci 8q24, 11q13, and 2p15 (P = 2.9 x 10(-4) to P = 4.7 x 10(-5)), showing study population power. We also find evidence to support reported associations at candidate genes RNASEL, EZH2, and NKX3-1 (P = 0.031 to P = 0.0085). We further explore a set of candidate genes related to RNASEL and to its role in retroviral restriction, identifying nominal associations at XPR1 and RBM9. The effects at 8q24 seem more pronounced for those diagnosed at an early age, whereas at 2p15 and RNASEL the effects were more pronounced at a later age. However, these trends did not reach statistical significance. The effects at 2p15 were statistically significantly more pronounced for those diagnosed with aggressive disease.
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PMID:Genetic variants and prostate cancer risk: candidate replication and exploration of viral restriction genes. 1956 9

Epidemiologic research conducted over the last two decades has led us to believe that inherited factors play an important role in the aetiology of prostate cancer, but the genes which underlie the inherited susceptibility are elusive. The most compelling associations to date are with genes involved in DNA damage repair, including BRCA2. In Poland we have initiated a programme to identify DNA variants which confer an increased risk of prostate cancer and other cancers. Here we review our recent results. We found that germline mutations in BRCA1, CHEK2 and NBS1 confer an increased prostate cancer risk in Polish men. We provide evidence that CHEK2 is a multi-organ cancer susceptibility gene. We show that inherited variation in RNASEL and MSR1 genes do not contribute to prostate cancer development in Poland.
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PMID:Selected aspects of inherited susceptibility to prostate cancer and tumours of different site of origin. 1972 94

Xenotropic murine leukemia virus-related virus (XMRV) was recently discovered in human prostate cancers and is the first gammaretrovirus known to infect humans. While gammaretroviruses have well-characterized oncogenic effects in animals, they have not been shown to cause human cancers. We provide experimental evidence that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to Moloney murine leukemia virus (MoMLV), another gammaretrovirus. We analyzed 334 consecutive prostate resection specimens, using a quantitative PCR assay and immunohistochemistry (IHC) with an anti-XMRV specific antiserum. We found XMRV DNA in 6% and XMRV protein expression in 23% of prostate cancers. XMRV proteins were expressed primarily in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. XMRV infection was associated with prostate cancer, especially higher-grade cancers. We found XMRV infection to be independent of a common polymorphism in the RNASEL gene, unlike results previously reported. This finding increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant to all individuals. Our observations provide evidence for an association of XMRV with malignant cells and with more aggressive tumors.
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PMID:XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. 2511 58

Prostate Cancer (CAP), is a complex disease with a multifactorial origin. It is characterized by heterogenous patterns of growth of neoplasic tissue, varying widely in its progression, age of beginning and therapy response. It is considered as the second most common cause of death by cancer in men and, it has been estimated, that one of five, suffers of CAP through the course of his life. The genetic etiology of neoplasic transformation of normal prostate cells is still not known; nevertheless, investigations in epidemiology have demonstrated a strong genetic component in its development, suggesting so much a pattern of mendelian inheritance as the presence of loci of susceptibility throughout the human genome. It has been described a cromosomic location related to the CAP in locus 1q24-25, denominated HPC1, where the gene RNASEL is located, and the seggregation of its alleles has been associated with the development of CAP in numerous familiar groups. The RNASEL gene codifies for a ribonuclease protein that degrades vi-ral and cellular ARN and takes part in the apoptosis. A decrease of the enzymatic activity up to three times in carriers of the G1385A polymorphism of this gene has been reported, and the same has been associated frequently with the development of CAP. Using a variant of the Polymerase Chain Reaction, Allele specific amplification, this investigation had as objective to determine the association between variant G1385A and CAP, in a sample of 103 masculine individuals with and without CAP, pertaining to the population of Maracaibo, Venezuela. An association between these variants and CAP could not be demonstrated.
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PMID:[G138A polymorphism of the RNASEL gene and its association with the development of prostate cancer. Preliminary study]. 1996 Oct 52

Three genes, namely, ELAC2 (HPC2 locus) on chromosome 17p11, 2'-5'-oligoisoadenlyate-synthetase-dependent ribonuclease L (RNASEL, HPC1 locus), and macrophage scavenger receptor 1 (MSR1) within a region of linkage on chromosome 8p, have been identified as hereditary tumor suppressor genes in prostate cancer. We genotyped 41 tagged single nucleotide polymorphisms (SNPs) covering the three genes in a case-control cohort, which included 1,436 Caucasians, 648 Hispanics, and 270 African Americans. SNPs within MSR1, ELAC2, and RNASEL were significantly associated with risk of prostate cancer albeit with differences among the three ethnic groups (P = 0.043-1.0 x 10(-5)). In Caucasians, variants within MSR1 and ELAC2 are most likely to confer prostate cancer risk, and rs11545302 (ELAC2) showed a main effect independent of other significant SNPs (P = 2.03 x 10(-5)). A major haplotype G-A-C-G-C-G combining five SNPs within MSR1 was further shown to increase prostate cancer risk significantly in this study group. Variants in RNASEL had the strongest effects on prostate cancer risk estimates in Hispanics and also showed an interaction effect of family history. In African Americans, single SNPs within MSR1 were significantly associated with prostate cancer risk. A major risk haplotype C-G-G-C-G of five SNPs within ELAC2 was found in this group. Combining high-risk genotypes of MSR1 and ELAC2 in Caucasians and of RNASEL and MSR1 in Hispanics showed synergistic effects and suggest that an interaction between both genes in each ethnicity is likely to confer prostate cancer risk. Our findings corroborate the involvement of ELAC2, MSR1, and RNASEL in the etiology of prostate cancer even in individuals without a family history.
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PMID:Single and multivariate associations of MSR1, ELAC2, and RNASEL with prostate cancer in an ethnic diverse cohort of men. 2008 12

The newly identified retrovirus-the xenotropic murine leukemia virus-related virus (XMRV)-has recently been shown to be strongly associated with familial prostate cancer in humans (A. Urisman et al., PLoS Pathog. 2:e25, 2006). While that study showed evidence of XMRV infection exclusively in the prostatic stromal fibroblasts, a recent study found XMRV protein antigens mainly in malignant prostate epithelial cells (R. Schlaberg et al., Proc. Natl. Acad. Sci. U. S. A. 106:16351-16356, 2009). To help elucidate the mechanisms behind XMRV infection, we show that prostatic fibroblast cells express Xpr1, a known receptor of XMRV, but its expression is absent in other cell lines of the prostate (i.e., epithelial and stromal smooth muscle cells). We also show that certain amino acid residues located within the predicted extracellular loop (ECL3 and ECL4) sequences of Xpr1 are required for efficient XMRV entry. Although we found strong evidence to support XMRV infection of prostatic fibroblast cell lines via Xpr1, we learned that XMRV was indeed capable of infecting cells that did not necessarily express Xpr1, such as those of the prostatic epithelial and smooth muscle origins. Further studies suggest that the expression of Xpr1 and certain genotypes of the RNASEL gene, which could restrict XMRV infection, may play important roles in defining XMRV tropisms in certain cell types. Collectively, our data reveal important cellular determinants required for XMRV entry into different human prostate cells in vitro, which may provide important insights into the possible role of XMRV as an etiologic agent in human prostate cancer.
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PMID:Evaluation of cellular determinants required for in vitro xenotropic murine leukemia virus-related virus entry into human prostate cancer and noncancerous cells. 2041 Feb 64

Xenotropic murine leukemia virus-related virus (XMRV) is an authentic, newly recognized human retrovirus first identified in prostate cancer tissues from men with a deficiency in the innate immunity gene RNASEL. At present, studies have detected XMRV at widely different rates in prostate cancer cases (0-27%) and in patients with chronic fatigue syndrome (CFS; 0-67%). Indirect or direct modes of carcinogenesis by XMRV have been suggested depending on whether the virus was found in stroma or malignant epithelium. Viral replication in the prostate might be affected by androgens, which stimulate XMRV through a transcriptional enhancer site in viral DNA. By contrast, host restriction factors, such as APOBEC3 and tetherin, inhibit virus replication. Immune dysfunction mediated by XMRV has been suggested as a possible factor in CFS. Recent studies show that some existing antiretroviral drugs suppress XMRV infections and diagnostic assays are under development. Although other retroviruses of the same genus as XMRV (gammaretroviruses) cause cancer and neurological disease in animals, whether XMRV is a cause of either prostate cancer or CFS remains unknown. Emerging science surrounding XMRV is contributing to our knowledge of retroviral infections while focusing intense interest on two major human diseases.
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PMID:The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. 2051 89


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