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  • CANCER  (15)
  • BREAST-CANCER  (13)
  • BREAST  (12)
  • polymorphism  (10)
  • COMMON VARIANTS  (9)
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  • 1
    Keywords: CANCER ; Germany ; POPULATION ; RISK ; GENES ; PROTEIN ; PROTEINS ; TRANSDUCTION ; PATIENT ; ACTIVATION ; MECHANISM ; IMPACT ; CARCINOGENESIS ; signal transduction ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; MUTATION ; SIGNAL-TRANSDUCTION ; cancer risk ; ONCOLOGY ; RE ; BRCA2 ; INCREASE ; analysis ; TESTS ; USA ; BINDING DOMAIN ; CANCER-RISK ; EPITHELIAL OVARIAN-CANCER ; KINASE-ANCHORING PROTEINS
    Abstract: Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous sing le-nucleotide polymorphisms that were predicted to be deleterious and found two (M4631, 1389G〉T and N2792S, 8375A〉G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M4631, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M4631 with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CL] = 1.08 to 1.27, P =.0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% Cl = 1.04 to 1.17, P=.001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% Cl = 1.12 to 1.45, P =.0003) and 1.16 (95% Cl = 1.06 to 1.27, P =.001)
    Type of Publication: Journal article published
    PubMed ID: 18334708
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  • 2
    Keywords: APOPTOSIS ; CANCER ; Germany ; NEW-YORK ; POPULATION ; RISK ; GENE ; ASSOCIATION ; polymorphism ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; DELETION ; NO ; PROMOTER ; REDUCED RISK ; cancer risk ; REGION ; case-control studies ; ONCOLOGY ; case-control study ; RE ; VARIANT ; PROMOTER POLYMORPHISM ; USA ; caspases ; PROMOTER REGION ; CANCER-RISK ; COMMON VARIANT ; breast cancer risk ; Sp1 binding site ; CASP8-652 6N del
    Abstract: A recent study on an Asian population reported a six-nucleotide insertion-deletion polymorphism (-652 6N del) in the CASP8 promoter region to be strongly associated with a decreased risk of multiple types of cancer, including breast cancer (BC). Here, we investigate the effect of this deletion in four independent large European BC case-control studies, including data from a total of 7,753 cases and 7,921 controls. The combined per allele odds ratio (OR) was 0.97 (95% confidence interval (CI), 95% CI = 0.93-1.02). The present result indicates that the CASP8 -652 6N del variant has no significant effect on BC risk in Europeans
    Type of Publication: Journal article published
    PubMed ID: 17891485
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  • 3
    Keywords: EXPRESSION ; GENE ; BREAST-CANCER ; OVARIAN-CANCER ; PROSTATE-CANCER ; telomere length ; COMMON VARIANT ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; FUNCTIONAL VARIATION
    Abstract: Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 x 10(-6) to P = 7.7 x 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 x 10(-18), CLPTM1L P = 1.5 x 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
    Type of Publication: Journal article published
    PubMed ID: 25487306
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  • 4
    Keywords: EXPRESSION ; BINDING ; GENOME-WIDE ASSOCIATION ; ESTROGEN-RECEPTOR-ALPHA ; CONFER SUSCEPTIBILITY ; RISK LOCUS ; COMMON VARIANTS ; FUNCTIONAL VARIANTS ; FOXA1 ; ANALYSES REVEAL
    Abstract: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
    Type of Publication: Journal article published
    PubMed ID: 25652398
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  • 5
    Keywords: TUMORS ; STABILITY ; ARCHITECTURE ; mammographic density ; GENOME-WIDE ASSOCIATION ; AUTOPHAGY ; COMMON VARIANTS ; BRCA2 MUTATION CARRIERS ; GENOTYPE IMPUTATION ; ZNF365
    Abstract: Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 10.82-0.881) and ER-negative (OR = 0.87 [0.82-0.911) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:0) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 10.91-0.951 and OR = 1.06 [1.03-1.091) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.131) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.961). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 26073781
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  • 6
    Keywords: CANCER ; COMMON ; DISEASE ; RISK ; RISKS ; GENE ; GENES ; primary ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; STAGE ; PATTERNS ; OVARIAN-CANCER ; SNP ; DATABASE ; Jun ; POPULATIONS ; familial risk ; BRCA2 MUTATIONS ; SUSCEPTIBILITY GENE ; SINGLE ; AGGREGATION ; VARIANT ; ALLELE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; CANCER SUSCEPTIBILITY ; ALLELES ; LEVEL ; familial aggregation ; single-nucleotide ; UNIT ; ENGLAND ; LOCI ; CHEK2-ASTERISK-1100DELC ; breast cancer susceptibility ; GENOME-WIDE ASSOCIATION ; association study ; GENETIC-SUSCEPTIBILITY ; GROWTH-FACTOR RECEPTOR-2
    Abstract: Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r(2) 〉 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P 〈 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P 〈 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach
    Type of Publication: Journal article published
    PubMed ID: 17529967
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  • 7
    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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  • 8
    Keywords: CANCER ; EXPRESSION ; DISEASE ; RISK ; GENE ; GENES ; ASSOCIATION ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; genetics ; familial risk ; USA ; LOCI ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; Genetic ; 33 ; COMMON VARIANTS ; Genome-wide association studies
    Abstract: Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage(1). To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q
    Type of Publication: Journal article published
    PubMed ID: 19330027
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  • 9
    Keywords: RECEPTOR ; CANCER ; MODEL ; BRCA1 ; OVARIAN-CANCER ; MUTATIONS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; GENOTYPE ; CHEK2-ASTERISK-1100DELC ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; FAMILY REGISTRY
    Abstract: Introduction: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. Methods: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. Results: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. Conclusions: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these
    Type of Publication: Journal article published
    PubMed ID: 21194473
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  • 10
    Keywords: POPULATION ; RISK ; TUMORS ; ASSOCIATION ; VARIANTS ; breast cancer ; SELECTION ; SUBTYPES ; breast cancer risk ; CONSORTIUM ; INVESTIGATORS ; MODIFIERS ; COMMON VARIANTS ; GENETIC-VARIANTS ; SUSCEPTIBILITY ALLELES ; ZNF365
    Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers
    Type of Publication: Journal article published
    PubMed ID: 23544013
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