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  • 1
    Keywords: CANCER ; MODEL ; PROSTATE ; DISEASE ; RISK ; GENE ; MARKER ; IMPACT ; BIOMARKERS ; ASSOCIATION ; LINKAGE ; polymorphism ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; STAGE ; IDENTIFICATION ; HEALTH ; SNP ; PROSTATE-CANCER ; MARKERS ; LINKAGE DISEQUILIBRIUM ; diabetes ; REPLICATION ; FUTURE ; DIABETES-MELLITUS ; ONCOLOGY ; VARIANT ; METAANALYSIS ; biomarker ; methods ; MULTIETHNIC COHORT ; LINKAGE-DISEQUILIBRIUM ; 8Q24 ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; genetic association ; SCAN ; Genetic ; COMMON VARIANTS ; Type ; single nucleotide ; RISK-ASSOCIATED LOCI
    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 = 2.14 x 10(-6)), with a suggestion of stronger association with aggressive disease (P = 1.2 x 10(-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 = 7.79 x 10(-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 = 1.60 x 10(-4) for aggressive cancer, n = 4,597; P = 3.25 x 10(-8) for non-aggressive 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. Cancer Epidemiol Biomarkers Prev; 19(5); 1349-55. (C)2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20406958
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  • 2
    Keywords: CANCER ; PROSTATE ; RISK ; MARKER ; ASSOCIATION ; SUSCEPTIBILITY ; SUSCEPTIBILITY LOCUS ; IDENTIFICATION ; genetics ; COLORECTAL-CANCER ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; cancer risk ; VARIANT ; CANCER SUSCEPTIBILITY ; CORE ; LOCUS ; USA ; CANCER-RISK ; 8Q24 ; GENOME-WIDE ASSOCIATION ; SCAN ; Genetic ; Genome-wide association studies ; RANGE ; MULTIPLE LOCI
    Abstract: We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. We identify a new association with prostate cancer risk on chromosome 8q24 (rs620861, P = 1.3 x 10(-10), heterozygote OR = 1.17, 95% CI 1.10-1.24; homozygote OR = 1.33, 95% CI 1.21-1.45). This defines a new locus associated with prostate cancer susceptibility on 8q24
    Type of Publication: Journal article published
    PubMed ID: 19767755
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  • 3
    Keywords: CANCER ; POPULATION ; RISK ; GENE-EXPRESSION ; SUSCEPTIBILITY ; VARIANTS ; IDENTIFICATION ; METAANALYSIS ; LOCUS ; 8Q24 ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; MULTIPLE LOCI ; HEPATOCYTE NUCLEAR FACTOR-1-BETA
    Abstract: Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P 〈 5 x 10(-8) with the most significant association with rs4430796 (P = 1.62 x 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2) = 0.64), rs7405696 was also associated with risk (P = 9.35 x 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 x 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 x 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer
    Type of Publication: Journal article published
    PubMed ID: 21576123
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  • 4
    Keywords: DISEASES ; VARIANTS ; IDENTIFICATION ; COLORECTAL-CANCER ; METAANALYSIS ; susceptibility loci ; CHALLENGES ; Consortia ; ASSOCIATION SCAN ; SARCOSINE
    Abstract: Background: No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS). Objective: To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer. Design, setting, and participants: SNPs implicated in any phenotype other than prostate cancer (p 〈= 10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24 534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Outcome measurements and statistical analysis: Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated. Results and limitations: A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p = 1.6 x 10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p = 3.22 x 10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p = 2.5 x 10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p = 4.67 x 10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL. Conclusions: We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology. Patient summary: We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified.
    Type of Publication: Journal article published
    PubMed ID: 25277271
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