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  • 1
    Keywords: DISEASE ; VARIANTS ; OVARIAN-CANCER ; BLADDER-CANCER ; LINKAGE DISEQUILIBRIUM ; METAANALYSIS ; GENETIC SUSCEPTIBILITY ; imputation ; RISK LOCI ; RECOMBINATION HOTSPOTS
    Abstract: We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 x 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 x 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 x 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 x 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 x 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 x 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
    Type of Publication: Journal article published
    PubMed ID: 25086665
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  • 2
    Keywords: RECEPTOR ; CANCER ; Germany ; PROSTATE ; COMMON ; COHORT ; RISK ; GENE ; GENES ; SAMPLE ; RELEASE ; RISK-FACTORS ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; prevention ; HEALTH ; WOMEN ; SNP ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; RISK FACTOR ; POPULATIONS ; genetic polymorphism ; EPIC ; nutrition ; CODE ; SINGLE ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; LEVEL ; HAPLOTYPE ; HORMONES ; TESTOSTERONE ; prospective ; RISK-FACTOR ; CANCER-RISK ; CIRCULATING LEVELS ; MULTIETHNIC COHORT ; BASE-LINE CHARACTERISTICS ; COMMON VARIANT ; LUTEINIZING-HORMONE ; androgens ; ESTROGENS ; CONSORTIUM ; androstenedione ; Genetic ; COMMON VARIANTS
    Abstract: Background: Gonadotropin releasing hormone (GNRH1) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3). Methods: We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms ( SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition ( EPIC), Multiethnic Cohort (MEC), Nurses' Health Study ( NHS), and Women's Health Study (WHS). Circulating levels of sex steroids ( androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects. Results: Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. Conclusion: Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians
    Type of Publication: Journal article published
    PubMed ID: 19640273
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  • 3
    Keywords: LUNG-CANCER ; DISEASE ; ENZYMES ; CLEAVAGE ; BETA-CAROTENE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; VITAMIN-A ; pooled analysis ; MENDELIAN RANDOMIZATION ; 15,15-MONOOXYGENASE
    Abstract: BACKGROUND: Dietary and circulating carotenoids have been inversely associated with breast cancer risk, but observed associations may be due to confounding. Single-nucleotide polymorphisms (SNPs) in beta-carotene 15,15'-monooxygenase 1 (BCMO1), a gene encoding the enzyme involved in the first step of synthesizing vitamin A from dietary carotenoids, have been associated with circulating carotenoid concentrations and may serve as unconfounded surrogates for those biomarkers. We determined associations between variants in BCMO1 and breast cancer risk in a large cohort consortium. METHODS: We used unconditional logistic regression to test four SNPs in BCMO1 for associations with breast cancer risk in 9,226 cases and 10,420 controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also tested weighted multi-SNP scores composed of the two SNPs with strong, confirmed associations with circulating carotenoid concentrations. RESULTS: Neither the individual SNPs nor the weighted multi-SNP scores were associated with breast cancer risk [OR (95% confidence interval) comparing extreme quintiles of weighted multi-SNP scores = 1.04 (0.94-1.16) for beta-carotene, 1.08 (0.98-1.20) for alpha-carotene, 1.04 (0.94-1.16) for beta-cryptoxanthin, 0.95 (0.87-1.05) for lutein/zeaxanthin, and 0.92 (0.83-1.02) for retinol]. Furthermore, no associations were observed when stratifying by estrogen receptor status, but power was limited. CONCLUSIONS: Our results do not support an association between SNPs associated with circulating carotenoid concentrations and breast cancer risk. Impact: Future studies will need additional genetic surrogates and/or sample sizes at least three times larger to contribute evidence of a causal link between carotenoids and breast cancer. Cancer Epidemiol Biomarkers Prev; 22(5); 927-36. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 23515144
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  • 4
  • 5
    Keywords: RECEPTOR ; CANCER ; COHORT ; RISK ; GENE ; MECHANISM ; MARKER ; RISK-FACTORS ; mechanisms ; BINDING ; CELL-LINES ; ASSOCIATION ; LINKAGE ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; prevention ; HEALTH ; WOMEN ; SNP ; risk factors ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; cancer risk ; DATABASE ; REGION ; REGIONS ; LINKAGE DISEQUILIBRIUM ; nutrition ; POSTMENOPAUSAL WOMEN ; PROGRAM ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; LOCUS ; single-nucleotide ; BLOCKS ; DEHYDROEPIANDROSTERONE-SULFATE ; SEX-HORMONE LEVELS ; prospective ; RISK-FACTOR ; CANCER-RISK ; MULTIETHNIC COHORT ; ANDROGEN ; BASE-LINE CHARACTERISTICS ; CAG REPEAT POLYMORPHISM ; COMMON VARIANT ; LINKAGE-DISEQUILIBRIUM ; NURSES HEALTH ; POLYGLUTAMINE TRACTS ; POSSIBLE MECHANISMS ; RECEPTOR GENE ; SET ; VITAMIN-D-RECEPTOR
    Abstract: Introduction Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/ or androgen receptor ( AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium ( BPC3). Methods The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships ( blocks) across the gene were then identified, and haplotypetagging single nucleotide polymorphisms ( htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts ( 5,603 breast cancer cases and 7,480 controls). Results We found no association between any genetic variation ( SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed. Conclusion Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer
    Type of Publication: Journal article published
    PubMed ID: 16987421
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  • 6
    Keywords: CANCER ; tumor ; carcinoma ; PROSTATE ; COMMON ; DIAGNOSIS ; COHORT ; MORTALITY ; RISK ; GENE ; GENES ; SAMPLE ; SAMPLES ; TUMORS ; validation ; MARKER ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; NO ; STAGE ; COMPARATIVE GENOMIC HYBRIDIZATION ; HEALTH ; DIFFERENCE ; AGE ; WOMEN ; MEN ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; REGION ; POPULATIONS ; CARRIERS ; case-control studies ; PREDICTORS ; LIFE-STYLE ; NESTED CASE-CONTROL ; SINGLE ; ONCOLOGY ; case control study ; case-control study ; RE ; VARIANT ; ALLELE ; GROWTH-FACTOR-I ; case control studies ; INTERVAL ; CARRIER ; GENOTYPE ; single-nucleotide ; USA ; NO ASSOCIATION ; cancer research ; CANCER-RISK ; MULTIETHNIC COHORT ; BASE-LINE CHARACTERISTICS ; nested case-control study ; case control ; case-control ; AFRICAN-AMERICAN
    Abstract: Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rsl447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 x 10(-13)). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 X 10(-13)). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an ORAC = 1.34 (99% confidence intervals, 1.19-1.50) and carriers with two copies of the minor allele had an ORAA = 1.86 (99% confidence intervals, 1.30-2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result
    Type of Publication: Journal article published
    PubMed ID: 17409400
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  • 7
    Keywords: CANCER ; PROSTATE ; COMMON ; CT ; SUPPORT ; COHORT ; POPULATION ; RISK ; GENE ; ASSOCIATION ; LINKAGE ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; ENCODES ; HEALTH ; WOMEN ; SNP ; MEN ; prostate cancer ; PROSTATE-CANCER ; LINE ; REGION ; LINKAGE DISEQUILIBRIUM ; POPULATIONS ; POSTMENOPAUSAL WOMEN ; SINGLE ; DEFICIENCY ; ONCOLOGY ; ASSOCIATIONS ; SNPs ; CANCER SUSCEPTIBILITY ; METAANALYSIS ; biomarker ; INTERVAL ; HAPLOTYPE ; HAPLOTYPES ; single-nucleotide ; USA ; HORMONES ; STEROID-HORMONES ; odds ratio ; cancer research ; MULTIETHNIC COHORT ; PREDICT ; steroids ; postmenopausal ; block ; HORMONE-LEVELS ; EXONS ; GENETIC-VARIATION ; ANDROGEN RECEPTOR GENE ; BRAZILIAN PATIENTS ; SERUM ANDROGENS
    Abstract: CYP17 encodes cytochrome p450c17 alpha, which mediates activities essential for the production of sex steroids. Common germ line variation in the CYP17 gene has been related to inconsistent results in breast and prostate cancer, with most studies focusing on the nonsynonymous single nucleotide polymorphism (SNP) T27C (rs743572). We comprehensively characterized variation in CYP17 by direct sequencing of exons followed by dense genotyping across the 58 kb region around CYP17 in five racial/ethnic populations. Two blocks of strong linkage disequilibrium were identified and nine haplotype-tagging SNPs, including T27C, were chosen to predict common haplotypes (R-h(2) 〉= 0.85). These haplotype-tagging SNPs were genotyped in 8,138 prostate cancer cases and 9,033 controls, and 5,333 breast cancer cases and 7,069 controls from the Breast and Prostate Cancer Cohort Consortium. We observed borderline significant associations with prostate cancer for rs2486758 [TC versus TT, odds ratios (OR), 1.07; 95% confidence intervals (95% Cl), 1.00-1.14; CC versus TT, OR, 1.09; 95% CI, 0.95-1.26; P trend = 0.04] and rs6892 (AG versus AA, OR, 1.08; 95% CI, 1.00-1.15; GG versus AA, OR, 1.11; 95% CI, 0.95-1.30; P trend = 0.03). We also observed marginally significant associations with breast cancer for rs4919687 (GA versus GG, OR, 1.04; 95% CI, 0.97-1.12, AA versus GG, OR, 1.17; 95% CI, 1.03-1.34; P trend = 0.03) and rs4919682 (CT versus CC, OR, 1.04; 95% CI, 0.97-1.12; TT versus CC, OR, 1.16; 95% CI, 1.01-1.33; P trend = 0.04). Common variation at CYP17 was not associated with circulating sex steroid hormones in men or postmenopausal women. Our findings do not support the hypothesis that common germ line variation in CYP17 makes a substantial contribution to postmenopausal breast or prostate cancer susceptibility
    Type of Publication: Journal article published
    PubMed ID: 18006912
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  • 8
    Keywords: DISEASE ; POPULATION ; RISK ; POLYMORPHISMS ; IDENTIFICATION ; METAANALYSIS ; telomere length ; LOCI ; GENOME-WIDE ASSOCIATION ; 5P15.33
    Abstract: A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 x 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 x 10(-5)), rs4583925 (p = 4.0 x 10(-5)) and rs2735948 (p = 5.0 x 10(-5)). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.
    Type of Publication: Journal article published
    PubMed ID: 25940397
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  • 9
    Abstract: PURPOSE: An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). PATIENTS AND METHODS: Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. RESULTS: Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] 〈 .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het 〈/= .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. CONCLUSION: The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.
    Type of Publication: Journal article published
    PubMed ID: 27325851
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  • 10
    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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