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  • 1
    Keywords: SPECTRA ; CANCER ; EXPRESSION ; LUNG-CANCER ; RISK ; SITE ; SITES ; ENZYMES ; GENE ; GENES ; METABOLISM ; PATIENT ; GENETIC POLYMORPHISMS ; tumour ; ASSOCIATION ; FREQUENCY ; polymorphism ; AGE ; MUTATION ; CIGARETTE-SMOKING ; bladder cancer ; BLADDER-CANCER ; p53 ; SWEDEN ; URINARY-BLADDER ; MUTATIONS ; CARRIERS ; CANCER PATIENTS ; GENE-MUTATIONS ; glutathione-S-transferase ; TRANSITIONAL-CELL CARCINOMA ; DNA-ADDUCTS ; ASSOCIATIONS ; TRANSITION ; TOBACCO-SMOKE ; CANCER SUSCEPTIBILITY ; TARGET GENE ; TARGET GENES ; GENETIC-POLYMORPHISM ; CARRIER ; p53 mutation ; SUPPRESSOR GENES ; SSCP
    Abstract: Genetic polymorphisms affecting expression or activity of the corresponding enzymes can influence the risk of acquiring gene mutations and various cancers. We have studied 327 bladder cancer patients with regard to the functionally related polymorphisms of GSTM1, GSTT1, GSTP1 and NAT2 and analysed the p53 mutational status of their tumours. Fifty p53 mutations, 26% transversions and 74% transitions, were detected in 44 patients. P53 mutation frequency was significantly higher in higher-grade tumours than in low-grade tumours (OR = 2.09, 95% CI 1.44-3.02, adjusted for age and sex). Also, a significant association was found between tumour stage (Tis and T2+ vs. Ta and T1) and presence of the GSTP1 val allele (adjusted OR = 2.00, CI 1.14-3.52). Overall, there was no significant difference in frequency of p53 mutation among patients with different genotypes. Among patients with p53 mutation, transversions were significantly more frequent in GSTM1-negative as compared to GSTM1-positive individuals (OR = 5.18, CI 1.07-25.02, adjusted for age, sex and tumour stage). With one exception, all tumours with the most common type of transversion, G:C-C:G, occurred in GSTM1-negative patients. Among smokers, all transversions (3 of 3), but only 2 of 13 transitions, were found among carriers of the GSTP1 variant allele, and samples carrying at least 1 variant GSTP1 allele had more transitions at CpG sites than wild-type samples (adjusted OR = 4.61, CI 0.82-26.04). No significant associations were found for the NAT2 gene. Our results suggest that impaired glutathione conjugation may affect the mutation spectrum in critical target genes. (C) 2004 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15499621
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  • 2
    Keywords: RISK ; POLYMORPHISMS ; smoking ; DNA-REPAIR GENES ; TRANSITIONAL-CELL CARCINOMA ; LOCI ; CHINESE POPULATION ; SEQUENCE VARIANTS ; CONFERS SUSCEPTIBILITY ; FLUID INTAKE
    Abstract: Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 x 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC
    Type of Publication: Journal article published
    PubMed ID: 21750109
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  • 3
    Keywords: EXPRESSION ; CELL ; LUNG-CANCER ; TUMORS ; HIGH-FREQUENCY ; UROTHELIAL CARCINOMA ; GENE PROMOTER ; THYROID-CANCER ; WHOLE-GENOME ; DISEASE RECURRENCE
    Abstract: Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR) = 4.93, 95% CI = 2.72-8.92, p 〈 0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p 〈 0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR = 2.15, 95% CI = 1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR = 3.68, 95%CI = 1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target.
    Type of Publication: Journal article published
    PubMed ID: 25809917
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  • 4
    Keywords: CELLS ; CELL ; human ; IN-VIVO ; PATHWAY ; PATHWAYS ; GENE ; GENES ; TIME ; DNA ; IMPACT ; recombination ; BASE ; polymorphism ; POLYMORPHISMS ; NO ; score ; ASSAY ; REPAIR ; genetics ; smoking ; SWEDEN ; COMET ASSAY ; DAMAGE ; LYMPHOCYTES ; DNA-DAMAGE ; MAMMALIAN-CELLS ; SAFETY ; INDIVIDUALS ; HEALTHY ; NUCLEOTIDE EXCISION-REPAIR ; heredity ; DNA repair ; EXCISION-REPAIR ; HOMOLOGOUS RECOMBINATION ; SINGLE-STRAND BREAKS ; HUMAN-LYMPHOCYTES ; VARIANT ; XPD ; XRCC1 ; ALLELES ; DNA damage ; USA ; LUNG-CANCER RISK ; base excision repair ; VARIANT ALLELES ; XRCC3 ; RATIO ; GENE POLYMORPHISMS ; alkaline comet assay ; GENE POLYMORPHISM ; NUCLEOTIDE ; CRUCIAL ROLE ; APEX1 ; methylmethane sulphonate ; POLYMERASE-BETA
    Abstract: We have applied the alkaline comet assay to study the functional impact of gene polymorphisms in base excision repair (APEX1 Asp148Glu, XRCC1 Arg194Trp, XRCC1 Arg399Gln) and homologous recombination repair (XRCC3 Thr-241Met, NBS1 Glu185Gln), two pathways that play crucial roles in the repair of DNA damage induced by methylmethane sulphonate (MMS). We also examined the effect of polymorphisms in mismatch repair (MLH1 -93 A/G) and nucleotide excision repair (XPD Lys751Gln) as putative negative controls based on the limited roles of these pathways in MMS-induced repair. Phyto-hemagglutinin-stimulated peripheral lymphocytes from 52 healthy individuals were treated with MMS and allowed to repair for 0, 15, 40, or 120 min after a 6-min washing step. DNA damage was measured as a pseudo-percentage score (comparable to % tail DNA) converted from a total visual score calculated from the distribution of cells with different degrees of damage (normal, mild, moderate and severe). The repair was faster at the beginning of the observation period than towards the end, and was not complete after 2 hr. Presence of the APEX1 148ASp, XRCC3 241Met or NBS1 185Gln alleles were significantly associated with a high pseudo-percentage score (above median) at early time points, with the APEX1 effect being most prolonged (up to 40 min after washing, odds ratio 5.6, 95% confidence interval 2.0-15.5). No significant effects were seen with the XRCC1 Arg194Trp, XRCC1 Arg399Gln, MLH1 -93A/G and XPD LyS751 Gln polymorphisms. Our results provide evidence for the functional nature of the variant alleles studied in the APEX1, XRCC3, and NBS1 genes. Environ. Mal. Mutagen. 49:669-675, 2008. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18627000
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  • 5
    Keywords: EXPRESSION ; RISK ; FAMILY ; BREAST-CANCER ; MELANOMA ; HUMAN TUMOR-CELLS ; TRANSCRIPTIONAL REGULATION ; WILD-TYPE P53 ; HTERT GENE ; TELOMERASE HTERT
    Abstract: The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions - 124 and - 146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.
    Type of Publication: Journal article published
    PubMed ID: 24101484
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  • 6
    Keywords: CANCER ; LUNG-CANCER ; EXPOSURE ; RISK ; GENE ; GENES ; PATIENT ; DNA ; CELL-CYCLE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; DNA-REPAIR ; MUTATION ; REPAIR ; bladder cancer ; BLADDER-CANCER ; p53 ; SWEDEN ; DAMAGE ; MUTATIONS ; CANCER-PATIENTS ; INDIVIDUALS ; CANCER PATIENTS ; SMOKERS ; DNA repair ; P53 MUTATIONS ; VARIANT ; XPD ; XRCC1 ; SSCP ; INCREASED RISK ; metabolism and repair ; QUINONE OXIDOREDUCTASE ; VARIANT ALLELES
    Abstract: We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin DI variant allele homozygotes (OR 2.4 Cl 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, Cl 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer. (c) 2005 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16343742
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  • 7
    Keywords: DNA ; GENES ; GENE ; DAMAGE ; DNA-DAMAGE ; ASSAY ; DNA-REPAIR ; REPAIR ; genetics ; POLYMORPHISMS ; polymorphism ; DNA repair ; heredity ; USA ; TOXICOLOGY ; mutagen
    Type of Publication: Meeting abstract published
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  • 8
    Keywords: CANCER ; COMBINATION ; LUNG ; lung cancer ; LUNG-CANCER ; POPULATION ; RISK ; GENE ; GENES ; PATIENT ; DNA ; recombination ; GENETIC POLYMORPHISMS ; ASSOCIATION ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; FREQUENCIES ; NUMBER ; AGE ; WOMEN ; DNA-REPAIR ; REPAIR ; smoking ; SWEDEN ; DAMAGE ; CANCER-PATIENTS ; case-control studies ; INDIVIDUALS ; CANCER PATIENTS ; SMOKERS ; DNA repair ; P53 MUTATIONS ; EXCISION-REPAIR ; ACID SUBSTITUTION VARIANTS ; HOMOLOGOUS RECOMBINATION ; DOUBLE-STRAND BREAKS ; case-control study ; VARIANT ; TOBACCO-SMOKE ; XPD ; XRCC1 ; case control studies ; INTERVAL ; GENETIC-POLYMORPHISM ; BASE EXCISION-REPAIR ; GENDER ; INCREASED RISK ; NEVER SMOKERS ; odds ratio ; homologous ; recombination repair ; low dose ; base excision repair ; non-smokers ; repair polymorphism ; XUAN-WEI
    Abstract: This case-control study examines the association between lung cancer and genetic polymorphisms in two base excision repair (BER) genes, XRCC1 and APEX1 and two genes involved in homologous recombination repair (HR), XRCC3 and NBS1. Never-smoking lung cancer patients were recruited, and also the next diagnosed ever-smoking case of the same gender and age group. Controls were recruited from the regional population register, frequency matched to cases by hospital catchment area, gender, age group and smoking category As a result more than 70% of the study population were women. A total of 331 individuals were analysed. Presence of the XRCC1 399Gln allele was associated with a significantly decreased risk for lung cancer among non-smoking women (odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2-0.9). No significant effect was seen with the APEX1 polymorphism. Women smokers carrying the XRCC3 241Met allele showed a significantly decreased risk for lung cancer (OR 0.3, CI 0.2-0.7). The NBS1 185Gln allele was significantly associated with an increased risk for lung cancer among non-smoking women (OR 2.2, CI 1.0-4.8) and low-dose smoking women (OR 4.8, CI 1.5-15.7). The protective effect of the variant XRCC3 241Met allele was strengthened when combined with the tow-risk Glu185 allele of the NBS1 gene. Smokers (OR 0.38, CI 0.16-0.90) and women (OR 0.42, Cl 0.21-0.85) with at least three Low-risk alleles in these two HR genes showed a significantly decreased risk for lung cancer. Thus, in spite of a relatively small study population, this study, including a comparatively large number of never-smokers and women, presents several novel aspects on genetic susceptibility to lung cancer. Our results show that the genetic variation in XRCC1, XRCC3 and NBS1 influence lung cancer susceptibility among women, and that combinations of risk alleles in the two HR genes can enhance the effects. (C) 2006 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17034901
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  • 9
    Keywords: SURVIVAL ; tumor ; neoplasms ; DIAGNOSIS ; FOLLOW-UP ; DISEASE ; RISK ; GENE ; GENES ; PATIENT ; CONTRAST ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; DNA-REPAIR ; p53 ; SWEDEN ; cancer risk ; MORPHOLOGY ; CARRIERS ; BEHAVIOR ; glutathione-S-transferase ; ASSOCIATIONS ; VARIANT ; ALLELE ; urothelial cancer ; GSTM1 ; MTHFR ; methods ; CARRIER ; PREDICT ; Urinary Bladder Neoplasms ; - ; comparison ; NONCARRIERS ; outcome ; CLINICAL-OUTCOMES ; GENE POLYMORPHISMS ; metabolic genes
    Abstract: Objective. Urinary bladder neoplasms differ considerably in biological potential, and tumor morphology alone cannot predict their clinical behaviors. Polymorphisms in xenobiotic metabolic genes reportedly modulate susceptibility to bladder neoplasms and may affect the clinical course and outcomes of the disease. This study was conducted to determine the effect of polymorphisms in the xenobiotic metabolic genes on the disease course and clinical outcomes of urinary bladder neoplasms. Material and methods. Patients with urinary bladder neoplasms who had been followed up for a 5-year period were genotyped for NQO1 (R139W, P187S), NAT (rapid/slow), GSTP1 (I105V), GSTT1 and GSTM1 (non-null/null) and MTHFR (A222V, E429A) polymorphisms. Results. Variant allele carriers of the NQO1 ( P187S) polymorphism showed a higher risk for high-stage disease than non-carriers at diagnosis [relative risk (RR) = 1.4; 95% CI 1.0-1.8). A higher risk for highly malignant disease (T2 +) was also observed in variant allele carriers than non-carriers of the GSTP1 (I105V) polymorphism (RR = 1.6; 95% CI 1.1 - 2.5). NQO1 (R139W) variant allele carrier patients with intermediate malignant disease (TaG3 + T1) had shorter disease-free survival than non-carriers (p = 0.05). In contrast, carriers of the variant allele for the MTHFR (A222V) polymorphism had significantly longer disease-free survival than non- carriers ( p = 0.02). Conclusions. Our data are consistent with the notion that NQO1 polymorphisms influence the course and clinical outcomes of urinary bladder neoplasms. However, our results need to be confirmed in a large study as most of the associations detected were only of marginal statistical significance, and would be lost on correction for multiple comparisons
    Type of Publication: Journal article published
    PubMed ID: 17469025
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  • 10
    Keywords: CANCER ; PROSTATE ; FOLLOW-UP ; LUNG-CANCER ; DISEASE ; NEW-YORK ; RISK ; GENE-EXPRESSION ; TIME ; SEQUENCE ; ASSOCIATION ; chromosome ; SIGNAL ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; NO ; genetics ; SNP ; PROSTATE-CANCER ; BLADDER ; bladder cancer ; BLADDER-CANCER ; NETHERLANDS ; INDIVIDUALS ; heredity ; VARIANT ; USA ; NOR ; CANCERS ; 8Q24 ; NOV ; UPSTREAM ; GENOME-WIDE ASSOCIATION ; association study ; RATIO ; NICOTINE DEPENDENCE ; GENOME-WIDE ; P63 EXPRESSION ; UROTHELIAL CELL-CARCINOMA
    Abstract: We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1.15 x 10(-7))
    Type of Publication: Journal article published
    PubMed ID: 18794855
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