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  • 1
    Abstract: Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P 〈 1 x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P 〈/= 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
    Type of Publication: Journal article published
    PubMed ID: 26732427
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  • 2
    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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  • 3
    Keywords: COHORT ; POPULATION ; RISK ; METAANALYSIS ; GTPASE-ACTIVATING PROTEIN ; BASE-LINE CHARACTERISTICS ; GENOME-WIDE ASSOCIATION ; SEQUENCE VARIANTS ; GLEASON SCORE ; LINKAGE SCAN
    Abstract: Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 x 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 x 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 x 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.
    Type of Publication: Journal article published
    PubMed ID: 25939597
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  • 4
    Abstract: BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p〈0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2〉0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p〈0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p〈0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
    Type of Publication: Journal article published
    PubMed ID: 28797570
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  • 5
    Keywords: CANCER ; GROWTH ; proliferation ; PATHWAY ; PROSTATE ; COHORT ; DISEASE ; HISTORY ; RISK ; GENE ; GENES ; FAMILY ; CARCINOGENESIS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; VARIANTS ; BREAST ; STAGE ; AGE ; OVARIAN-CANCER ; SNP ; MEN ; PROSTATE-CANCER ; FACTOR-I ; CELL-MIGRATION ; PHOSPHOINOSITIDE 3-KINASE ; signaling ; ONCOLOGY ; REGRESSION ; ASSOCIATIONS ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; GROWTH-FACTOR-I ; BINDING PROTEIN-3 ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; PHOSPHATIDYLINOSITOL 3-KINASE ; FACTOR (IGF)-I ; pooled analysis ; FAMILY-HISTORY ; INCREASED RISK ; CANCER-RISK ; genetic association ; single nucleotide ; REGULATORY SUBUNIT
    Abstract: The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking, and may affect prostate carcinogenesis. Thus, we explored the association between single-nucleotide polymorphisms (SNP) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk [ORper (allele), 1.08 (95% CI, 1.03-1.14); P-trend = 0.0017] after adjustment for multiple testing (P-adj = 0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association [ORper (allele), 1.21 (95% CI, 1.09-1.34); P-trend = 0.0003]. The adjusted association was stronger for men who were diagnosed before the age of 65 years [ORper (allele), 1.47 (95% CI, 1.20-1.79); P-trend = 0.0001] or had a family history [ORper (allele) = 1.57 (95% CI, 1.11-2.23); P-trend = 0.0114], and was strongest in those with both characteristics [ORper (allele) = 2.31 (95% CI, 1.07-5.07), P-interaction = 0.005]. Increased risks were observed among men in the top tertile of circulating insulin-like growth factor-I (IGF-I) levels [ORper (allele) = 1.46 (95% CI, 1.04-2.06); P-trend = 0.075]. No differences were observed with disease aggressiveness (Gleason grade = 8 or stage T-3/T-4 or fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early-onset disease, which may be attributable to IGF-dependent PI3K signaling. Cancer Res; 70(6); 2389-96. (C)2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20197460
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  • 6
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  64. Kongress der Nordrhein-Westfälischen Gesellschaft für Urologie; 20180322-20180323; Düsseldorf; DOCV 1.3 /20180215/
    Publication Date: 2018-02-26
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 7
    Publication Date: 2018-01-17
    Description: Objectives Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. We evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators. Methods Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. We used multivariate logistic regression to estimate ORs and 95% CIs for subclinical hypothyroidism (TSH 〉4.5 mIU/L) compared with normal TSH (0.4- 〈 4.5 mIU/L) and for anti-TPO positivity. We also examined pesticide associations with TSH, T4 and T3 in multivariate linear regression models. Results Higher exposure to the insecticide aldrin (third and fourth quartiles of intensity-weighted days vs no exposure) was positively associated with subclinical hypothyroidism (OR Q3 =4.15, 95% CI 1.56 to 11.01, OR Q4 =4.76, 95% CI 1.53 to 14.82, p trend 〈0.01), higher TSH (p trend =0.01) and lower T4 (p trend =0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: OR Q4 =2.78, 95% CI 1.30 to 5.95, p trend =0.02), higher TSH (p trend =0.04) and anti-TPO positivity (p trend =0.01). The fumigant methyl bromide was inversely associated with TSH (p trend =0.02) and positively associated with T4 (p trend =0.01). Conclusions Our results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators.
    Print ISSN: 1351-0711
    Electronic ISSN: 1470-7926
    Topics: Medicine
    Published by BMJ Publishing Group
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