SNPs in the kallikrein gene region associated with prostate cancer risk: true cause or association by design?
Ontology highlight
ABSTRACT:
SUBMITTER: Eeles R
PROVIDER: S-EPMC3882634 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND:Epidemiological studies have assessed the association between kallikrein 3 (KLK3) polymorphisms and prostate cancer (PCa) susceptibility. However, published data on this association are somewhat inconclusive. METHODS:Articles investigating the association between three KLK3 (rs1058205, rs2735839, and rs266882) variants and PCa susceptibility were searched from online databases, which included 35,838 patients and 36,369 control participants. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to demonstrate the strength of the association. We also utilized ELISA to detect serum expression of KLK3. In addition, in silico tools were adopted to evaluate the relationship of KLK3 expression and PCa survival time. RESULTS:The overall results indicated that polymorphism T>C of rs1058205 was associated with decreased risk of PCa (allele contrast: OR = 0.75, 95% CI = 0.64-0.88, P heterogeneity < 0.001; homozygote comparison: OR = 0.58, 95% CI = 0.42-0.81, P heterogeneity < 0.001), particularly in Caucasian population (allele contrast: OR = 0.77, 95% CI = 0.65-0.91, P heterogeneity < 0.001; homozygote comparison: OR = 0.58, 95% CI = 0.41-0.82, P heterogeneity < 0.001). No association was observed between the polymorphism A>G of rs2735839 and risk of PCa. In addition, no association was observed between polymorphism A>G of rs266882 and risk of PCa. Serum KLK3 levels in PCa patients carrying CC/CT genotypes were statistically lower than those carrying TT genotypes. Conclusion: This meta-analysis suggests that rs1058205 polymorphism of KLK3 is a risk factor for PCa development, polymorphism T>C of rs1058205 is associated with decreased susceptibility to PCa particularly in Caucasian population.
| S-EPMC6265624 | biostudies-literature
Project description:A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding
| PRJEB4865 | ENA
Project description:Additional prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) continue to be identified. It is unclear whether addition of newly identified SNPs improves the discriminative performance of biopsy outcomes over previously established SNPs.A total of 667 consecutive patients that underwent prostate biopsy for detection of PCa at Huashan Hospital and Changhai Hospital, Shanghai, China were recruited. Genetic scores were calculated for each patient using various combinations of 29 PCa risk-associated SNPs. Performance of these genetic scores for discriminating prostate biopsy outcomes were compared using the area under a receiver operating characteristic curve (AUC).The discriminative performance of genetic score derived from a panel of all 29 SNPs (24 previous and 5 new) was similar to that derived from the 24 previously established SNPs, the AUC of which were 0.60 and 0.61, respectively (P = 0.72). When SNPs with the strongest effect on PCa risk (ranked based on contribution to the total genetic variance from an external study) were sequentially added to the models for calculating genetic score, the AUC gradually increased and peaked at 0.62 with the top 13 strongest SNPs. Under the 13-SNP model, the PCa detection rate was 21.52%, 36.74%, and 51.98%, respectively for men with low (<0.5), intermediate (0.5-1.5), and high (>1.5) genetic score, P-trend = 9.91 × 10(-6).Genetic score based on PCa risk-associated SNPs implicated to date is a significant predictor of biopsy outcome. Additional small-effect PCa risk-associated SNPs to be discovered in the future are unlikely to further improve predictive performance.
| S-EPMC3910089 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified more than 30 single nucleotide polymorphisms (SNPs) that were reproducibly associated with prostate cancer (PCa) risk in populations of European descent. In aggregate, these variants have shown potential to predict risk for PCa in European men. However, their utility for PCa risk prediction in Chinese men is unknown.We selected 33 PCa risk-related SNPs that were originally identified in populations of European descent. Genetic scores were estimated for subjects in a Chinese case-control study (1,108 cases and 1,525 controls) based on these SNPs. To assess the performance of the genetic score on its ability to predict risk for PCa, we calculated area under the curve (AUC) of the receiver operating characteristic (ROC) in combination with 10-fold cross-validation.The genetic score was significantly higher for cases than controls (P?=?5.91?×?10(-20)), and was significantly associated with risk of PCa in a dose-dependent manner (P for trend: 4.78?×?10(-18)). The AUC of the genetic score was 0.604 for risk prediction of PCa in Chinese men. When ORs derived from this Chinese study population were used to calculate genetic score, the AUCs were 0.631 for all 33 SNPs and 0.617 when using only the 11 significant SNPs.Our results indicate that genetic variants related to PCa risk may be useful for risk prediction in Chinese men. Prospective studies are warranted to further evaluate these findings.
| S-EPMC3232337 | biostudies-literature
Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin . Genomic profile of androgen receptor binding sites of androgen or vehicle treated DUCaP cells using ChIP-seq. IgG precipiated DNAs from both treatments served as controls.
2015-07-10 | E-GEOD-70679 | biostudies-arrayexpress
Project description:In a population-based case-control study, we explored the associations between 42 polymorphisms in seven genes in this region and non-small cell lung cancer (NSCLC) risk among Caucasian (364 cases; 380 controls) and African American (95 cases; 103 controls) women. Two TERT region SNPs, rs2075786 and rs2853677, conferred an increased risk of developing NSCLC, especially among African American women, and TERT-rs2735940 was associated with a decreased risk of lung cancer among African Americans. Five of the 20 GHR polymorphisms and SEPP1-rs6413428 were associated with a marginally increased risk of NSCLC among Caucasians. Random forest analysis reinforced the importance of GHR among Caucasians and identified AMACR, TERT, and GHR among African Americans, which were also significant using gene-based risk scores. Smoking-SNP interactions were explored, and haplotypes in TERT and GHR associated with NSCLC risk were identified. The roles of TERT, GHR, AMACR and SEPP1 genes in lung carcinogenesis warrant further exploration.
| S-EPMC2861408 | biostudies-literature
Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin .
2015-07-10 | GSE70679 | GEO
Project description:Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC).A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform.No relation to risk was found. Three SNPs were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171G>A (p = 0.003; n = 30; hazard ratio [HR]: 0.307), GSTP1 rs1799811C>T (p = 0.001; n = 38; HR: 0.254) and SLC5A6 rs1395 (p = 0.004; n = 35; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387C>T (p = 0.039) and ABCC5 rs939339A>G (p = 0.018).This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis.
| S-EPMC5558514 | biostudies-other
Project description:Several genome-wide association studies (GWAS) of prostate cancer (PCa) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with PCa risk in various racial groups. The objective of this study is to evaluate which of these SNPs are associated with PCa risk in Chinese men and estimate their strength of association.All SNPs that were reported to be associated with PCa risk in GWAS from populations of European, African American, Japanese, and Chinese descent were evaluated in 1,922 PCa cases and 2,175 controls selected from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). A logistic regression analysis was used to estimate allelic odds ratios (ORs) of these SNPs for PCa.Among the 53 SNPs, 50 were polymorphic in the Chinese population. Of which, 10 and 24 SNPs were significantly associated with PCa risk in Chinese men at P?<?0.001 and <0.05, respectively. These 24 significant SNPs included 17, 5, and 2 SNPs that were originally discovered in European, Japanese, and Chinese descent, respectively. The estimated ORs ranged from 1.10 to 1.49 and the direction of association was consistent with previous studies. When ORs were estimated separately for PCa with Gleason score ?7 and ?8, a marginally significant difference in ORs was found only for two of the 24 SNPs (P?=?0.02 and 0.04).About half of PCa risk-associated SNPs identified in GWAS of various populations are associated with PCa risk in Chinese men. Information on PCa risk-associated SNPs and their ORs may facilitate risk assessment of PCa risk in Chinese men.
| S-EPMC3928594 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified dozens of genomic loci, whose single nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the biological functions of these common genetic variants and the mechanisms to increase disease risk are largely unknown. We integrated chromatin-IP coupled sequencing (ChIP-seq) and microarray expression profiling in the TMPRSS2-ERG gene rearrangement positive DuCaP cell model with the NHGRI GWAS PCa risk SNPs catalog, in an attempt to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Among the 48 GWAS index SNPs and 2,702 linked SNPs defined by the 1000G project 104 were found to be localized in the AR ChIP-seq peaks. Of these risk SNPs, rs11891426 T/G in the 7th intron of its host gene melanophilin (MLPH) was found located within a putative auxiliary ARE motif, which we found enriched in the neighborhood of canonical ARE motifs. Exchange of T to G attenuated the transcriptional activity of the MLPH-ARBS in a reporter gene assay. The expression of MLPH protein in tissue samples from prostate cancer patients was significantly lower in those with the G compared to the T allele. Moreover, a significant positive correlation of AR and MLPH protein expression levels was also confirmed in tissue samples. These results unravel a hidden link between AR and a functional PCa risk SNP rs11891426, whose allele alteration affects androgen regulation of its host gene MLPH. This study shows the power of integrative studies to pin down functional risk SNPs and justifies further investigations.
2015-10-12 | GSE63693 | GEO