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  • 1
    Keywords: CANCER ; EXPRESSION ; Germany ; PATHWAY ; RISK ; GENE ; transcription ; PATIENT ; FAMILY ; TRANSCRIPTION FACTOR ; MARKER ; ASSOCIATION ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; SNP ; cancer risk ; COLORECTAL CANCERS ; case-control studies ; INDIVIDUALS ; beta-catenin ; C-MYC ; TYPE-2 ; WNT ; CYCLIN D1 ; signaling ; case-control study ; RE ; FAMILIES ; VARIANT ; case control studies ; ROLES ; CANCER-RISK ; FAMILIAL BREAST ; familial breast cancer ; GENETIC ALTERATION ; Wnt signaling ; type 2 diabetes
    Abstract: Background: The transcription factor 7-like 2 (TCF7L2) is a critical component of the Wnt/beta-catenin pathway. Aberrant TCF7L2 expression modifies Wnt signaling and mediates oncogenic effects through the upregulation of c-MYC and cyclin D. Genetic alterations in TCF7L2 may therefore affect cancer risk. Recently, TCF7L2 variants, including the microsatellite marker DG10S478 and the nearly perfectly linked SNP rs12233372, were identified to associate with type 2 diabetes. Methods: We investigated the effect of the TCF7L2 rs12255372 variant on familial breast cancer ( BC) risk by means of TaqMan allelic discrimination, analyzing BRCA1/2 mutation-negative index patients of 592 German BC families and 735 control individuals. Results: The T allele of rs12255372 showed an association with borderline significance ( OR = 1.19, 95% C. I. = 1.01-1.42, P = 0.04), and the Cochran-Armitage test for trend revealed an allele dose-dependent association of rs12255372 with BC risk ( P-trend = 0.04). Conclusion: Our results suggest a possible influence of TCF7L2 rs12255372 on the risk of familial BC
    Type of Publication: Journal article published
    PubMed ID: 17109766
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  • 2
    Keywords: APOPTOSIS, APOPTOSIS-INDUCING LIGAND, ASSOCIATION, BINDING, BREAST, breast cancer, BREAST-CANCER, CA
    Abstract: Dysregulation of apoptosis plays a crucial role in carcinogenesis. Tumour necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptotic pathway by binding to death receptor 4 (DR4). Thus, genetic alterations within the candidate tumour suppressor gene DR4 would be expected to provoke a deficient apoptotic signalling thereby facilitating the development of cancer. The DR4 variants Thr209Arg and Glu228Ala were genotyped in a series of 521 breast cancer cases and 1100 control subjects from Germany, determining their impact on breast cancer risk. Neither Thr209Arg (626C 〉 G) nor Glu228Ala (683A 〉 C) alone were significantly associated with breast cancer risk [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.65-1.08, P = 0.18 and OR = 0.89, 95% CI = 0.72-1.12, P = 0.30]. However, haplotype analysis revealed a 3.5-fold risk for carriers of the 626C-683C haplotype (OR = 3.52, 95% CI = 1.45-8.52, P = 0.003)
    Type of Publication: Journal article published
    PubMed ID: 15975957
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  • 3
    Keywords: RECEPTOR ; SIMULATIONS ; APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; LUNG-CANCER ; screening ; DEATH ; POPULATION ; RISK ; GENE ; TIME ; LIGAND ; SIMULATION ; BINDING ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; VARIANTS ; BREAST-CANCER ; STAGE ; AGE ; colorectal cancer ; COLORECTAL-CANCER ; cancer risk ; PREVALENCE ; RECEPTORS ; APOPTOSIS-INDUCING LIGAND ; RECTAL-CANCER ; RE ; TUMOR-SUPPRESSOR ; VARIANT ; SUPPRESSOR GENE ; INCREASE ; cell proliferation ; INTERVAL ; tumor suppressor gene ; TESTS ; death receptor ; LINKAGE PHASE ; CANDIDATE ; population-based ; general population ; CANCER-RISK ; RARE ; NECROSIS ; APO2L/TRAIL
    Abstract: The tumor necrosis factor-related apoptosis-inducing ligand receptor modulates apoptotic response by binding to the proapoptotic death receptor 4 (DR4). Perturbed apoptosis due to missense alterations in the candidate tumor suppressor gene DR4 leads to deregulated cell proliferation and cancer predisposition. Recent studies have discussed the association of DR4 variants with cancer risk. We evaluated, for the first time, the role of the Thr(209)Arg (626C 〉 G) and Glu(228)AIa (683A 〉 C) polymorphisms on colorectal cancer risk by genotyping 659 incident cases and 607 healthy controls drawn from the German population-based Darmkrebs: Chancen der Verhutung durch Screening (DACHS) study. Whereas DR4 Glu(228)Ala was not associated with colorectal cancer, Thr(209)Arg heterozygotes were at a significantly decreased colorectal cancer risk [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54-0.97]. Stratification according to sex and age exhibited a significant association of Thr(209)Arg with a decreased risk for male heterozygotes (OR, 0.68; 95% CI, 0.46-0.99) and for Arg(209) carriers 〉= 65 years of age (OR, 0.65; 95% CI, 0.46-0.92) as well as an enhanced risk for female Ala(228) carriers in a allele dose-dependent manner (P-trend = 0.01). Subsite analysis revealed a protective effect of Thr(209)Arg for rectal cancer risk (OR, 0.67; 95% CI, 0.48-0.95) and a significant risk increase for Ala 228 carriers with advanced colorectal cancer stages (P-trend = 0.04). Haplotype analysis revealed a 2.4-fold risk for carriers of the rare 626C-683C haplotype (1% prevalence in the general population; OR, 2.37; 95% CI, 0.98-5.76). The score statistic yielded an empirical P of 0.03 of the haplotype-specific test for 626C-683C based on 20,000 simulations, suggesting that DR4 626C-683C may affect colorectal cancer predisposition
    Type of Publication: Journal article published
    PubMed ID: 17035413
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  • 4
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; Germany ; human ; PATHWAY ; screening ; RISK ; GENE ; GENES ; PROTEIN ; PROTEINS ; TIME ; PATIENT ; LIGAND ; CARCINOGENESIS ; colon ; DOWN-REGULATION ; ASSOCIATION ; SUSCEPTIBILITY ; TARGET ; NO ; PROGRESSION ; colorectal cancer ; COLORECTAL-CANCER ; BLADDER-CANCER ; HETEROZYGOSITY ; cancer risk ; COLON-CANCER ; LIGANDS ; CARCINOMAS ; CARRIERS ; INDIVIDUALS ; beta-catenin ; RECEPTORS ; WNT ; signaling ; ONCOLOGY ; RE ; VARIANT ; HUMAN CANCER ; TUMORIGENESIS ; FAMILIAL BREAST-CANCER ; INTERVAL ; TARGET GENES ; rectal cancer ; HUMAN CANCERS ; INCREASED RISK ; CANCERS ; CANCER-RISK ; colorectal ; SFRP1
    Abstract: The Wnt-beta-catenin pathway plays a central role in colorectal tumorigenesis. Frizzled-related protein (FRZB, also termed secreted frizzled-related protein 3, sFRP3) antagonizes the signaling of wingless (Wnt) ligands through the frizzled membrane-bound receptors, resulting in beta-catenin destabilization thereby suppressing the expression of target genes. Recently, the FRZB Gly324 variant has been shown to have an attenuated ability to antagonize Wnt signaling and to be associated with an increased osteoarthritis risk. Here, we investigated, for the first time, the role of Arg324Gly (970C〉G) along with Arg200Trp (598C〉T) on colorectal cancer (CRC) risk by analyzing 659 patients and 607 control individuals drawn from the German DACHS (Darmkrebs: Chancen der Verhu " tung durch Screening) study. Although Arg200Trp showed no effect on CRC risk, we found homozygous carriers of Gly324 more frequent in cases than in controls, leading to a significantly increased risk for CRC [odds ratio (OR) = 5.1, 95% confidence interval (95% CI) = 1.74-14.71, P 〈 0.001]. The association was stronger in rectal cancer (OR = 7.52, 95% CI = 2.40-23.25, P 〈 0.0001) than in colon cancer (OR = 3.66, 95% CI = 1.14-11.76, P 〈 0.05). Since modified Wnt signaling and down-regulation of frizzled-related proteins have been observed in many human cancers, this variant may also affect the susceptibility to other cancers
    Type of Publication: Journal article published
    PubMed ID: 17420170
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