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 candidate prostate cancer susceptibility gene HPC2/ELAC2 has two common coding polymorphisms: (Ser-->Leu 217) and (Ala-->Thr 541). The Thr541 variant in the HPC2/ELAC2 gene has previously been reported to be at an increased frequency in prostate cancer cases. To evaluate this hypothesis we genotyped 432 prostate cancer patients (including 262 patients diagnosed <or=55 years) and 469 UK, population based control individuals with no family history of cancer. We found no significant difference in the frequencies of Thr541-containing genotypes between cases and controls (OR=1.41, 95% CI 0.79-2.50). The association remained non-significant when the analysis was restricted to cases divided by age of onset into those diagnosed <or=55 years (OR=1.50, 95% CI 0.79-2.85) or to patients diagnosed >55 years (OR=1.27, 95% CI 0.59-2.74). We conclude that any association between the Thr541 variant and prostate cancer is likely to be weak.
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PMID:HPC2/ELAC2 polymorphisms and prostate cancer risk: analysis by age of onset of disease. 1237 7

The recently identified prostate cancer susceptibility gene ELAC2 ( HPC2) harbors two common missense variants, a serine to leucine substitution at residue 217 (Leu217) and an alanine to threonine substitution at residue 541 (Thr541). We genotyped the two variants in a Japanese cohort consisting of 350 prostate cancer patients 242 male population controls, and 114 male low-risk controls. Both missense alleles, Leu217 and Thr541, were carried at higher frequency in Japanese patients than in the controls (Leu217, P= 0.0012; Thr541, P = 0.0145), and the odds ratios associated with carrying these sequence variants were higher in Japanese than in Caucasians. Although the Leu217 and Thr541 variants of ELAC2 are less common in Japanese than in Caucasians, both variants confer significantly increased risk of prostate cancer in Japanese. Carriage of these variants was not associated with age at diagnosis, tumor stage, or tumor grade in these Japanese prostate cancer patients. The allele-specific pattern of risk observed in Japanese and familial Caucasian patients was qualitatively similar; however, the magnitude of that risk was considerably greater in Japanese than in Caucasians.
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PMID:Association of common missense changes in ELAC2 ( HPC2) with prostate cancer in a Japanese case-control series. 1252 85

In most developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that the role of candidate genetic markers to this multifactorial malignancy is more difficult to identify than the identification of other cancer susceptibility genes. Indeed, despite the localization of several susceptibility loci, there has been limited success in identifying high-risk susceptibility genes analogous to BRCA1 or BRCA2 for breast and ovarian cancer. Nonetheless, three strong candidate susceptibility genes have been described, namely ELAC2 (chromosome 17p11/HPC2 region), 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL), a gene in the HPC1 region, and Macrophage Scavenger Receptor 1 (MSR1), a gene within a region of linkage on chromosome 8p. Additional studies using larger cohorts are needed to fully evaluate the role of these susceptibility genes in prostate cancer risk. It is also of interest to mention that a significant percentage of men with early-onset prostate cancer harbor germline mutation in the BRCA2 gene thus confirming its role as a high-risk prostate cancer susceptibility gene. Although initial segregation analyses supported the hypothesis that a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, current experimental evidence better supports the hypothesis that some of the familial risks may be due to inheritance of multiple moderate-risk genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants in some of those genes.
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PMID:Prostate cancer susceptibility genes: lessons learned and challenges posed. 1279 Jul 86

The HPC2/ELAC2 gene may be associated with hereditary/familial prostate cancer (PCa). Two common missense variants (Ser217Leu and Ala541Thr) have been reported in the gene. We performed mutational, allelotyping and expression analyses and a molecular epidemiological study to clarify the relations between this gene and prostatic diseases, including PCa and benign prostatic hyperplasia (BPH) in Japanese men. We screened for mutations in 109 patients with PCa including 11 patients from 1 hereditary and 9 familial PCa. Loss of heterozygosity and expression were analyzed. An epidemiological study was done in sporadic PCa (n=98) and BPH (n=143) using 1 novel (Ser627Leu) and 2 previously described polymorphisms of the HPC2/ELAC2 gene. Somatic or germline mutations were not confirmed in any cases of PCa. Loss of heterozygosity at 2 microsatellites, D17S1289 and D17S520, was detected in 1 of 38 and 1 of 35 cases, respectively. Expression analysis revealed decreased or absent mRNA expression in 6 of 38 tumors. Epidemiologic analysis showed that a Leu allele at codon 217 was significantly more frequent in patients with PCa than in controls (10.2% vs. 3.5%, odds ratio = 3.11; 95% confidence interval, 1.22-7.90). At codon 541, all patients with PCa or BPH and all control subjects had the Ala/Ala genotype. At codon 627, the incidence of the Leu variant was slightly, but not significantly, higher in patients with BPH than in controls (7.0% vs. 2.8%, odds ratio = 2.59, 95% confidence interval, 0.94-7.13, not statistically significant). We concluded that germline/somatic mutations of HPC2/ELAC2 are uncommon in PCa. Similarly, allelic imbalances at the gene locus and changes in expression are rare. Although no difference in allele frequency at Ser217Leu between patients with PCa and controls has been reported in a Western population, this polymorphism is a potential indicator of PCa risk in Japanese men and it should be examined in other ethnic groups.
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PMID:Ser217Leu polymorphism of the HPC2/ELAC2 gene associated with prostatic cancer risk in Japanese men. 1294 98

Genetic polymorphism in HPC2/ELAC2 was recently associated with risk of sporadic prostate cancer. To determine the contribution of two HPC2/ELAC2 missense variants (Ser217Leu and Ala541Thr) to the risk of developing prostate cancer, we conducted a population-based case-control study of middle-aged men (40-64 years). Cases (n=591) were ascertained from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results Cancer Registry and Controls (n=538) from the same general population were identified through random-digit dialing. Subjects were residents of King County, Washington, and were frequency matched on age. Cases (32%) had a slightly higher frequency of the Leu217 variant compared with controls (29%), but there were no differences in the frequency of the Thr541 allele (4%). When considering joint genotypes, white men homozygous for the Leu217 variant on an Ala541/Ala541 background had an increased risk of prostate cancer [odds ratio (OR)=1.84; 95% confidence interval (CI), 1.11-3.06]. Different risk profiles were also observed when cases were stratified by disease aggressiveness. Men with at least one Leu217 allele had an elevated risk (OR=1.34; 95% CI, 1.02-1.76) of less aggressive prostate cancer (localized stage and Gleason score < or = 7), with a stronger association among men with two Leu217 alleles (OR=1.73; 95% CI, 1.08-2.77). The Ala541Thr polymorphism was not associated with risk, and neither variant was associated with more aggressive prostate cancer phenotypes. We estimate that the Ser217Leu genotype may account for approximately 14% of less aggressive prostate cancer cases and 9% of all sporadic cases in the general United States population of white men <age 65 years.
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PMID:Association of HPC2/ELAC2 polymorphisms with risk of prostate cancer in a population-based study. 1450 98

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD - ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis >/= 66 years; maximum LOD - ZLR = 2.82), with <5 affected family members (LOD - ZLR = 3.02), with presence of hereditary prostate cancer (LOD - ZLR = 2.81), or with no male-to-male transmission of disease (LOD - ZLR = 3.84). No other chromosome showed significant evidence for linkage. However, chromosomes 6 and X showed suggestive results, with maximum LOD - ZLR values of 1.38 and 1.36, respectively. Subset analyses suggest additional chromosomal regions worth further follow-up.
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PMID:Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study. 1460 Oct 30

The HPC2/ELAC2 gene on chromosome 17p11 was identified as a candidate gene for hereditary prostate cancer (HPC) susceptibility. Two HPC2 gene missense variants, Ser217Leu (Leu217) and Ala541Thr (Thr541) have been associated with incident prostate cancer cases in some studies, but not in others. We tested for possible associations between the two HPC2 gene variants and prostate cancer risk in incident prostate cancer cases (199) and healthy male controls (525) from the Calgary region. The Thr541 variant showed linkage disequilibrium with the Leu217 variant. The number of Leu217 homozygotes in the case and control groups (8.6 versus 8.5%) was not statistically different. Leu217 carrier status was associated with prostate cancer risk (cases 61.8% versus controls 50.3%) (OR 1.6, 95% CI 1.15-2.23). Additional analysis found that this association was not due to the co-existence of Thr541 variant (OR1.59, P=0.009). Logistic regression found that the relationship between the log odds of being a Thr541carrier and age depends on case/control status. Thr541 carriers had an increased risk for late-onset prostate cancer (P=0.028). Prostate intraepithelial neoplasia (PIN) was more common in the Leu217 allele carriers compared to non-carriers (42.3 versus 26.7%) (OR 2.05, 95% CI 1.10-3.83), and in the Thr541 carriers compared to non-carriers (50.0 versus 34.6%) (OR 1.89, 95% CI 0.75-4.78). In summary, the HPC2 gene variants Leu217 and Thr541 were associated with an increased risk for prostate cancer and for PIN in males undergoing radical prostatectomies in the Calgary region.
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PMID:HPC2/ELAC2 gene variants associated with incident prostate cancer. 1462 8

Three putative prostate cancer-susceptibility genes, RNASEL/HPC1 at 1q24, MSR1 at 8p22, and ELAC2/HPC2 at 17p11, have recently been identified. Our objective was to investigate somatic mutations in these genes in sporadic prostate cancer. We analyzed 39 clinical prostate cancer specimens, 10 prostate cancer xenografts (LuCaP series), and 4 prostate cancer cell lines (LNCaP, DU145, PC-3, and MPC-3) for genetic changes using denaturing high-performance liquid chromatography and direct sequencing in order to screen the whole coding regions of RNASEL and MSR1, as well as exons 7 and 17 of ELAC2. The known 471delAAAG truncating mutation was found in the RNASEL gene in cell line LNCaP. The only new missense variation in RNASEL, Gly296Val, was found in cell line DU145, but not in any other samples. RNASEL and ELAC2 also showed the common missense polymorphic changes. A previously reported truncating mutation (Arg293X) was found in MSR1 in the germ line of one individual. Our results indicate that inactivation of the RNASEL, ELAC2, or MSR1 genes by somatic mutation is a rare phenomenon in sporadic prostate cancer.
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PMID:Mutational analysis of susceptibility genes RNASEL/HPC1, ELAC2/HPC2, and MSR1 in sporadic prostate cancer. 1469 91

Prostate cancer is the most frequent cancer among men in most developed countries, yet little is known about its causes. Older age, African ancestry and a positive family history of prostate cancer have long been recognized as important risk factors. The evidence that genetics probably plays a critical role is based on a variety of study designs, including case-control, cohort, twin and family-based, all of which are reviewed in detail. The search for prostate cancer susceptibility genes by linkage studies offered early hope that finding genes would be as 'easy' as finding genes for breast cancer and colon cancer susceptibilities. However, this hope has been dampened by the difficulty of replicating promising regions of linkage. This review provides updates on recent developments, and a broad view of the disparate findings from different linkage studies. Early linkage results have provided targeted candidate regions for prostate cancer susceptibility loci, including HPC1 on chromosome 1q23-25, PCAP on chromosome 1q42-43, CAPB on chromosome 1p36, linkage to chromosome 8p22-23, HPC2 on chromosome 17p, HPC20 on chromosome 20q13, and HPCX on chromosome Xq27-28. These linkage findings lead to refined mapping and mutation screening of several strong candidate genes, including ELAC2, RNASEL and MSR1. Up to now, a total of 10 genome-wide linkage scans for prostate cancer susceptibility have been completed, and are reviewed. Furthermore, recent findings that Gleason's grade, a measure of aggressiveness of prostate cancer, is linked to several genomic regions are reviewed. Finally, the roles of environmental and dietary risk factors, and common genetic polymorphisms of genes likely to play a role in common forms of prostate cancer, are briefly discussed within in the context of searching for genes that influence prostate cancer risk.
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PMID:The complex genetic epidemiology of prostate cancer. 1474 51

Reported associations of ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer have been inconsistent and understudied in African Americans. We evaluated the role of 16 sequence variants in these genes with prostate cancer using 888 European American and 131 African American cases, and 473 European American and 163 African American, controls. We observed significant differences in ELAC2, RNASEL, and MSR1 allele frequencies by race. However, we did not observe significant associations between prostate cancer and any variants examined for both races combined. Associations were observed when stratified by race, family history, or disease severity. European American men homozygous for MSR1 IVS7delTTA had an elevated risk for localized stage [odds ratio, (OR), 3.5; 95% confidence interval (95% CI), 1.4-6.9], low-grade (OR, 3.2; 95% CI, 1.4-7.3) disease overall, and with low-grade (OR, 2.9; 95% CI, 1.2-7.2) or late-stage disease (OR, 5.2; 95% CI, 1.1-25.7) in family history-negative African Americans. MSR1 Arg293X was associated with family history-negative high-grade disease (OR, 4.0; 95% CI, 1.1-14.1) in European Americans. RNASEL Arg462Gln was associated with low-grade (OR, 1.5; 95% CI, 1.04-2.2) and early-stage (OR, 1.5; 95% CI, 1.02-2.1) disease in family history-negative European Americans. In family history-positive individuals, Arg462Gln was inversely associated with low-grade (OR, 0.43; 95% CI, 0.21-0.88) and low-stage (OR, 0.46; 95% CI, 0.22-0.95) disease. In African Americans, Arg462Gln was associated with positive family history high-stage disease (OR, 14.8; 95% CI, 1.6-135.7). Meta-analyses revealed significant associations of prostate cancer with MSR1 IVS7delTTA, -14,742 A>G, and Arg293X in European Americans; Asp174Tyr in African Americans; RNASEL Arg462Gln in European American's overall and in family history-negative disease; and Glu265X in family history-positive European Americans. Therefore, MSR1 and RNASEL may play a role in prostate cancer progression and severity.
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PMID:Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men. 1582 69


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