Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The human ELAC2 gene was the first candidate prostate cancer susceptibility gene identified by linkage analysis and positional cloning. DNA sequence indicates a protein of 826 amino acids encoded by 24 exons. In the present study, we characterized the coding sequence of chimpanzee and gorilla ELAC2 orthologs by direct sequencing of genomic fragments, and of cynomolgus monkey and rat orthologs by screening cDNA libraries. The orthologs characterized in the chimpanzee, gorilla and cynomolgus monkey also encode proteins of 826 amino acids, sharing 98.9%, 98.5% and 93.7% sequence identity with the human protein. Our analyses of the mouse ELAC2 gene identified two alternative mRNA transcripts. One is translated into a protein of 824 a.a. (mouse ELAC2), whereas the other one encodes a protein of 831 amino acids (mouse ELAC2A) resulting from an alternatively spliced form of 25 exons. The rat ELAC2 gene ortholog also expressed two similar alternatively spliced transcripts. These two forms are ubiquitously expressed in mouse and rat tissues. The highest levels of expression of the ELAC2 form are observed in the testis while the lowest levels are seen in the prostate and in the muscle. However, it is of interest to note that the relative abundance of the rat and mouse ELAC2 transcripts, measured by real-time quantitative PCR, is higher than the respective ELAC2A forms in all surveyed tissues except for the prostate and the muscle. The ELAC2A transcript levels are 4.1 to 5.0-fold higher than the ELAC2 levels in the prostate of rat and mouse, respectively. A fine analysis of the conserved domains on the primary structure of ELAC2 orthologs revealed the presence of a putative beta-CASP domain shared by the PSO2 (SNM1) DNA interstrand cross-link repair proteins, and the 73-kDa subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73) as well as Artemis proteins, thus suggesting a potential interaction of ELAC2 gene product with nucleic acids and more specifically with RNA targets. Taken together, these data offer useful tools to further study the regulation and cellular function of ELAC2 gene in experimental models and provide further insight concerning conserved amino acid motifs that could have biological significance.
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PMID:Structure of primate and rodent orthologs of the prostate cancer susceptibility gene ELAC2. 1535 15

Prostate cancer is the most common malignancy and the second leading cause of cancer death among men in the United States. There are three well-established risk factors for prostate cancer: age, race and family history. The molecular bases for these risk factors are unclear; however, they may be influenced by epigenetic events. Epigenetic events covalently modify chromatin and alter gene expression. Methylation of cytosine residues within CpG islands on gene promoters is a primary epigenetic event that acts to suppress gene expression. In tumorigenesis, the normal functioning of the epigenetic-regulatory system is disrupted leading to inappropriate CpG island hypermethylation and aberrant expression of a battery of genes involved in critical cellular processes. Cancer-dependent epigenetic regulation of genes involved in DNA damage repair, hormone response, cell cycle control and tumor-cell adhesion/metastasis can contribute significantly to tumor initiation, progression and metastasis and, thereby, increase prostate cancer susceptibility and risk. In this review, we will discuss current research on genes that are hypermethylated in human prostate cancer. We will also discuss the potential involvement of DNA methylation in age-related, race-related and hereditary prostate cancer, and the potential use of hypermethylated genes as biomarkers to detect prostate cancer and assess its risk.
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PMID:DNA methylation in prostate cancer. 1536 62

About 10% of the prostate cancer cases were recognized as familial or hereditary. Till now gene/genes responsible for hereditary prostate cancer are not identified. Hereditary prostate cancer case concerning 3 brothers in family of 6 siblings from first marriage and a grandson from second marriage was presented. Two brothers were treated radical prostatectomy because of confined disease. The third brother with spreading disease died after androgen blockade management. We did not find any linkage between chosen markers of PCaP region (Predisposing for Prostate Cancer) and prostate cancer occurrence in this family.
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PMID:[Hereditary prostate cancer]. 1551 Aug 98

Prostate cancer is a complex disease with a substantial genetic contribution involved in the disease risk. Several genomewide linkage studies conducted so far have demonstrated a strong heterogeneity of susceptibility. In order to assess candidate regions that are particularly relevant for the German population, we performed a genomewide linkage search on 139 prostate cancer families. A nonparametric method (Zlr scores), using GENEHUNTERPLUS, was applied at 500 markers (panel P1400, deCODE), with an average spacing of 7.25 cM. In the entire family collection, linkage was most evident at 8p22 (Zlr=2.47, P=0.0068), close to the previously identified susceptibility gene MSR1. Further local maxima with Zlr>2 (P<0.025) were observed at 1q, 5q and 15q. In a subgroup of 47 families, which matched the Johns Hopkins criteria of hereditary prostate cancer, suggestive linkage was found on 1p31 (Zlr=3.37, P=0.00038), a previously not described candidate region. The remaining 92 pedigrees, with no strong disease history, revealed a maximum Zlr=3.15 (P=0.00082) at 8q13, possibly indicating a gene with reduced penetrance or recessive inheritance. Our results suggest pronounced locus heterogeneity of prostate cancer susceptibility in Germany. In the present study population, the MSR1 gene could play a significant role. Other conspicuous loci, like 1p31 and 8q13, need further investigation in order to verify their relevance and to identify candidate genes.
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PMID:A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany. 1553 76

In a recent genome-wide linkage (GWL) analysis of Finnish families at high risk for prostate cancer, we found two novel putative susceptibility loci at 3p25-p26 and 11q14. Here, we report the fine-mapping of these two critical regions at high resolution with 39 microsatellite markers in 16 families, including multiplex families that were not used in the GWL scan. The maximum multipoint HLOD was 3.39 at 3p26 and 1.42 at 11q14. The highest LOD scores were seen around markers D3S1270 and D3S4559 (alpha=0.89), covering approximately two megabases. The two known genes in this region CHL1 (cell adhesion molecule with homology to L1CAM) and CNTN6 (contactin 6) were screened for exonic mutations in the families showing the strongest linkage, but no disease-segregating sequence variants were observed. The recombination map pointed to a region proximal to the area of best linkage, suggesting that more genes may need to be investigated as candidates. These results provide strong evidence for the existence of a prostate cancer susceptibility gene at 3p26 in Finnish prostate cancer families. This locus has not been strongly linked with hereditary prostate cancer in other populations. However, the mildly positive 3p LOD scores in a recent GWL analysis of patients from the United States suggest that the locus may also be important in other populations.
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PMID:Hereditary prostate cancer in Finland: fine-mapping validates 3p26 as a major predisposition locus. 1554 92

In association analyses, it is critical that informative single-nucleotide polymorphisms (SNPs) be selected for study and utilized appropriately. We sequenced 38 kb, including exons of ELAC2, promoter region and conserved upstream intergenic sequences. A comprehensive characterization of linkage disequilibrium (LD) structure and mutation history was performed using our principal components analysis (PCA) method and a phylogenetic analysis. We identified a complex pattern of LD structure consistent with the occurrence of both recombination and mutation events within ELAC2. Four overlapping and noncontiguous LD groups were defined. Eight tagging SNPs (tSNPs) were identified, accounting for over 90% of the genetic variation of the 19 total variants. We tested associations between familial early-onset prostate cancer (PRCA) and each variant independently and in haplotypes. We performed these tests using all 19 variants and the 8 tSNPs; the results using tSNP haplotypes accurately represent the association evidence for the full haplotypes. We observed increased evidence for association when SNPs were analyzed in haplotypes. The phylogenetic analysis indicated three haplotypes, clustered farthest from the root-node, all of which were found more often in cases than controls. These three haplotypes together showed the best evidence of association with familial, early-onset PRCA (P=0.0024; odds ratio=2.23; 95% CI, 1.33-3.74), indicating possible allelic heterogeneity. Our results suggest that 8 tSNPs are required to comprehensively assess associations in ELAC2, and that haplotypes should be considered for analysis, and that a knowledge of mutation history may be helpful in parsing allelic heterogeneity and suggesting combinations of haplotypes to be tested.
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PMID:Characterization of linkage disequilibrium structure, mutation history, and tagging SNPs, and their use in association analyses: ELAC2 and familial early-onset prostate cancer. 1559 91

The International Consortium for Prostate Cancer Genetics (ICPCG) is an international collaborative effort to pool pedigrees with hereditary prostate cancer (PC) in order to replicate linkage findings for PC. A strength of the ICPCG is the large number of well-characterized pedigrees, allowing linkage analyses within large subsets. Given the heterogeneity and complexity of PC, the historical difficulties of synthesizing different studies reporting positive and negative linkage replication, and the use of different statistical analysis methods and different stratification criteria, the ICPCG provides a valuable resource to evaluate linkage for hereditary PC. To date, linkage of chromosome 20 (HPC20) to hereditary PC has been one of the strongest linkage signals, yet the efforts to replicate this linkage have been limited. This paper reports a linkage analysis of chromosome 20 markers for 1,234 pedigrees with multiple cases of PC ascertained through the ICPCG, and represents the most thorough attempt to confirm or refute linkage to chromosome 20. From the original 158 Mayo pedigrees in which linkage was detected, the maximum heterogeneity LOD (HLOD) score, under a recessive model, was 2.78. In contrast, for the 1,076 pedigrees not included in the original study, the maximum HLOD score (recessive model) was 0.06. Although, a few small linkage signals for chromosome 20 were found in various strata of this pooled analysis, this large study failed to replicate linkage to HPC20. This study illustrates the value of the ICPCG family collection to evaluate reported linkage signals and suggests that the HPC20 region does not make a major contribution to PC susceptibility.
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PMID:Description of the International Consortium For Prostate Cancer Genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13. 1559 43

The hereditary prostate cancer 1 (HPC1) allele maps to the RNASEL gene encoding a protein (RNase L) implicated in the antiviral activity of interferons. To investigate the possible role of RNase L in apoptosis of prostate cancer cells, we decreased levels of RNase L by severalfold in the DU145 human prostate cancer cell line through the stable expression of a small interfering RNA (siRNA). Control cells expressed siRNA with three mismatched nucleotides to the RNase L sequence. Cells deficient in RNase L, but not the control cells, were highly resistant to apoptosis by the RNase L activator, 2',5'-oligoadenylate (2-5A). Surprisingly, the RNase L-deficient cells were also highly resistant to apoptosis by combination treatments with a topoisomerase (Topo) I inhibitor (camptothecin, topotecan, or SN-38) and tumor necrosis factor-related apoptosis-inducing ligand [TRAIL (Apo2L)]. In contrast, cells expressing siRNA to the RNase L inhibitor RLI (HP68) showed enhanced apoptosis in response to Topo I inhibitor alone or in combination with TRAIL. An inhibitor of c-Jun NH(2)-terminal kinases reduced apoptosis induced by treatment with either 2-5A or the combination of camptothecin and TRAIL, thus implicating c-Jun NH(2)-terminal kinase in the apoptotic signaling pathway. Furthermore, prostate cancer cells were sensitive to apoptosis from the combination of 2-5A with either TRAIL or Topo I inhibitor, whereas normal prostate epithelial cells were partially resistant to apoptosis. These findings indicate that RNase L integrates and amplifies apoptotic signals generated during treatment of prostate cancer cells with 2-5A, Topo I inhibitors, and TRAIL.
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PMID:HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. 1560 85

To date, germline mutations have been found in three candidate genes for hereditary prostate cancer: ELAC2 at 17p11, RNASEL at 1q25 and MSR1 at 8p22. RNASEL, encoding the 2',5'-oligoadenylate-dependant RNase L, seems to have rare mutations in different ethnicities, such as M1I in Afro-Americans, E265X in men of European descent and 471delAAAG in Ashkenazi Jews. In order to evaluate the relevance of RNASEL in the German population, we sequenced its open reading frame to determine the spectrum and frequency of germline mutations. The screen included 303 affected men from 136 Caucasian families, of which 45 met the criteria for hereditary prostate cancer. Variants were analysed using a family-based association test, and genotyped in an additional 227 sporadic prostate cancer patients and 207 controls. We identified only two sib pairs (1.4% of our families) cosegregating conspicuous RNASEL variants with prostate cancer: the nonsense mutation E265X, and a new amino-acid substitution (R400P) of unknown functional relevance. Both alleles were also found at low frequencies (1.4 and 0.5%, respectively) in controls. No significant association of polymorphisms (I97L, R462Q and D541E) was observed, neither in case-control analyses nor by family-based association tests. In contrast to previous reports, our study does not suggest that common variants (i.e. R462Q) modify disease risk. Our results are not consistent with a high penetrance of deleterious RNASEL mutations. Due to the low frequency of germline mutations present in our sample, RNASEL does not have a significant impact on prostate cancer susceptibility in the German population.
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PMID:Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene. 1571 8

To identify genes that generally increase the risk of cancer, we performed a systematic search throughout the genome in 188 families primarily ascertained for prostate cancer but which also included individuals with other cancers. We observed significant evidence for linkage between susceptibility to all cancers and markers at 3p24, with a peak HLOD of 3.08 (P=0.0002). Compared to families with less than three other cancers and prostate cancer only, evidence for linkage at this region was stronger among families with at least three other cancers. This is the first reported example of a genome-wide search for general cancer susceptibility genes among hereditary prostate cancer families.
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PMID:Evidence for a general cancer susceptibility locus at 3p24 in families with hereditary prostate cancer. 1572 17


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