Dataset Information

Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2.

ABSTRACT: BACKGROUND:Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P=2.14x10(-6)), with a suggestion of stronger association with aggressive disease (P=1.2x10(-7)). METHODS:In the third stage of genome-wide association studies, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry. RESULTS:The strongest association was observed with the initial marker rs10486567, which now achieves genome-wide significance [P=7.79x10(-11); ORHET, 1.19 (95% confidence interval, 1.12-1.27); ORHOM, 1.37 (95% confidence interval, 1.20-1.56)]. We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (P=1.60x10(-4) for aggressive cancer, n=4,597; P=3.25x10(-8) for nonaggressive cancer, n=4,514). Based on a multilocus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140; P=0.587), body stature (rs849141, tagged by rs849136; P=0.171), and risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142; P=0.657). CONCLUSION:rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry. IMPACT:Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa.

SUBMITTER: Prokunina-Olsson L

PROVIDER: S-EPMC2866032 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2.

Prokunina-Olsson Ludmila L Fu Yi-Ping YP Tang Wei W Jacobs Kevin B KB Hayes Richard B RB Kraft Peter P Berndt Sonja I SI Wacholder Sholom S Yu Kai K Hutchinson Amy A Spencer Feigelson Heather H Thun Michael J MJ Diver W Ryan WR Albanes Demetrius D Virtamo Jarmo J Weinstein Stephanie S Schumacher Fredrick R FR Cancel-Tassin Geraldine G Cussenot Olivier O Valeri Antoine A Andriole Gerald L GL Crawford E David ED Haiman Christopher A CA Henderson Brian E BE Kolonel Laurence L Le Marchand Loic L Siddiq Afshan A Riboli Elio E Travis Ruth R Kaaks Rudolf R Isaacs William B WB Isaacs Sarah D SD Grönberg Henrik H Wiklund Fredrik F Xu Jianfeng J Vatten Lars J LJ Hveem Kristian K Kumle Merethe M Tucker Margaret M Hoover Robert N RN Fraumeni Joseph F JF Hunter David J DJ Thomas Gilles G Chatterjee Nilanjan N Chanock Stephen J SJ Yeager Meredith M

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20100420 5

<h4>Background</h4>Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P=2.14x10(-6)), with a suggestion of stronger association with aggressive disease (P=1.2x10(-7)).<h4>Method ...[more]

PMID: 20406958

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Project description:The objective of Human Y Chromosome Proteome Project is to map and annotate all proteins encoded by genes on the MSY sequences. Lysine (K)-specific demethylase 5D (KDM5D) is located on the AZFb region of Y chromosome and encode for a JmjC-domain-containing protein. Changes in KDM5D transcript level in prostate cancer have shown in various studies. To investigation the function of KDM5D in prostate cancer, we knocked down the expression of KDM5D in human prostate cancer cell (DU-145) using siRNA approach. Down-regulation of KDM5D was confirmed by qRT-PCR and western-blot analyses. Cell cycle analysis and MTS assay revealed that down-regulation of KDM5D induces cell proliferation. Furthermore, we observed that KDM5D down-regulation could effectively decrease apoptosis, as measured by the propidium iodide flow cytometric assay. To further our study, we investigated the dynamic of KDM5D protein network using shotgun label free quantitative proteomics approach in knockdown and control cell line. In summary, 102 down-regulated and 107 up-regulated proteins were detected from 894 total proteins. Up-regulated proteins mainly activated ribosome biogenesis whereas down-regulated genes were mainly involved in proteolysis, cell death and metabolic process. The result raw files were converted to mzXML format and processed through the global proteome machine (GPM) software (version 2.1.1) of the X!Tandem algorithm (freely available at http://www.thegpm.org). The 16 gel fractions were processed serially for each experiment and the output files were generated as non-redundant, merged files with protein identifications with log (e) values less than -1, for each individual gel fraction. A protein database compiled from NCBI (Homo sapien) was used in GPM to search the tandem mass spectra; the database also included common trypsin and human peptide contaminants. False discovery rates (FDR) were evaluated by searching against a reversed sequence database. Search parameters included MS and MS/MS tolerances of +2 Da and +0.2 Da, carbamidomethylation of cysteine as fixed modifications, oxidation of methionine as variable modifications and tolerance of two missed tryptic cleavages and K/R-P cleavages.

Dataset Information

Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2.

Publications

Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2.

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