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  • GENE  (17)
  • EXPRESSION  (11)
  • 1
    Keywords: CANCER ; Germany ; DISEASE ; RISK ; GENE ; GENOME ; RNA ; ASSOCIATION ; polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; NO ; OVARIAN-CANCER ; WOMEN ; MUTATION ; cancer risk ; REGION ; genotyping ; MUTATIONS ; case-control studies ; ONCOLOGY ; case-control study ; REGRESSION ; RE ; FAMILIES ; PENETRANCE ; analysis ; methods ; SUPPRESSOR ; GENOTYPE ; BRCA1 MUTATION CARRIERS ; BIRTH ; CANCER-RISK ; FRAGMENT ; ENGLAND ; comparison ; Rb ; UNTRANSLATED REGION
    Abstract: Background: The variable penetrance of ovarian cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify disease risk. The C to T transition in the 3' untranslated region of the prohibitin ( PHB) gene alters mRNA function and has recently been shown to be associated with hereditary breast cancer risk in Polish women harbouring BRCA1 mutations. Methods: To investigate whether the PHB 3' UTR polymorphism also modifies hereditary ovarian cancer risk, we performed a case-control study among Polish women carrying one of the three common founder mutations (5382insC, 300 T 〉 G, 4154delA) including 127 ovarian cases and 127 unaffected controls who had both breasts and ovaries intact. Controls were matched to cases by year of birth and BRCA1 mutation. Genotyping analysis was performed using PCR-based restriction fragment length polymorphism analysis. Odds ratios ( OR) were calculated using conditional and penalized univariable and multivariable logistic regression. Results: A comparison of the genotype frequencies between cases and controls revealed no association of the PHB 3'UTR_CT+TT genotypes with ovarian cancer risk ( ORadj 1.34; 95% CI, 0.59-3.11). Conclusion: Our data suggest that the PHB 3' UTR polymorphism does not modify ovarian cancer risk in women carrying one of the three Polish BRCA1 founder mutations
    Type of Publication: Journal article published
    PubMed ID: 18397521
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  • 2
    Keywords: APOPTOSIS ; CANCER ; carcinoma ; CELL ; LUNG ; MODEL ; PATHWAY ; PATHWAYS ; lung cancer ; LUNG-CANCER ; RISK ; GENE ; GENES ; METABOLISM ; CARCINOGENESIS ; ASSOCIATION ; SUSCEPTIBILITY ; VARIANTS ; AGE ; DNA-REPAIR ; smoking ; ADHESION ; CELL-ADHESION ; inflammation ; ONCOLOGY ; case-control study ; REGRESSION ; ASSOCIATIONS ; VARIANT ; CANDIDATE GENES ; METHYLENETETRAHYDROFOLATE REDUCTASE ; INCREASED RISK ; SQUAMOUS-CELL ; CHINESE POPULATION ; XUAN-WEI ; METHYLENE-TETRAHYDROFOLATE REDUCTASE ; GENE POLYMORPHISMS ; Genetic ; CENTRAL-EUROPE ; SEQUENCE VARIANTS
    Abstract: Background. Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3). Methods. Genotype data from 15 ILCCO case-control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk. Results. Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10(-4)). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11 722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89-0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85-0.95), P = 1 x 10(-4)]. Conclusion. This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations
    Type of Publication: Journal article published
    PubMed ID: 20106900
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  • 3
    Keywords: RECEPTOR ; CANCER ; DISEASE ; RISK ; GENE ; ALLELES ; 8Q24 ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONSORTIUM ; TUMOR SUBTYPES ; URIC-ACID NEPHROLITHIASIS
    Abstract: Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 x 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 x 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 x 10(-3)). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
    Type of Publication: Journal article published
    PubMed ID: 22351618
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  • 4
    Keywords: EXPRESSION ; transcription ; CHROMATIN ; WOMEN ; REVEALS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; AFRICAN-AMERICAN ; ESTROGEN-RECEPTOR BINDING ; DETERMINANT
    Abstract: The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ER alpha to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.
    Type of Publication: Journal article published
    PubMed ID: 24290378
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  • 5
    Keywords: EXPRESSION ; REDUCED RISK ; HUMAN GENES ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; BINDING-SITES ; COMMON VARIANT ; CASP8 GENE ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; IDENTIFIES 3
    Abstract: Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
    Type of Publication: Journal article published
    PubMed ID: 25390939
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  • 6
    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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  • 7
    Keywords: EXPRESSION ; carcinoma ; polymorphism ; BREAST-CANCER ; COLON-CANCER ; GENOME-WIDE ASSOCIATION ; UDP-GLUCURONOSYLTRANSFERASES ; IRON TRANSPORT ; FAMILY SLC25 ; HEPHAESTIN
    Abstract: BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q〈0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p〈0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
    Type of Publication: Journal article published
    PubMed ID: 26091520
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  • 8
    Keywords: CANCER ; DISEASE ; POPULATION ; RISK ; SITE ; SITES ; GENE ; GENES ; REDUCTION ; ASSOCIATION ; polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; prevention ; MALIGNANCIES ; AGE ; BRCA1 ; ovarian cancer ; OVARIAN-CANCER ; WOMEN ; MUTATION ; REPAIR ; cancer risk ; REGION ; MUTATIONS ; POPULATIONS ; SERIES ; MALIGNANCY ; FAMILIES ; PENETRANCE ; MUTATION CARRIERS ; single-nucleotide polymorphism ; CANCER-RISK ; RAD51 ; OVARIAN ; PREDICT ; NONCARRIERS
    Abstract: Breast and ovarian cancer penetrance in BRCA1 mutation carriers is estimated to be between 15% and 80% by age 70 years. At present, it is not possible to predict with any certainty who is most likely to develop disease or which age it will develop. Previous studies have tried to correlate the sites of BRCA1 mutations with disease risk; however, the results have not yielded any definitive association. An alternative explanation that could account for differences in the penetrance of BRCA1 mutations is the action of modifier genes. In this study, we have investigated the role of the RAD51_135+_G 〉 C polymorphism in breast and ovarian cancer case-control populations of Polish women who have been matched for BRCA1 mutation and year of birth. The results reveal that women who harbor the C allele have almost twice the reduction in breast and ovarian cancer risk compared with women who harbor only the G allele. These findings suggest that the effect of the RAD51 C allele is an important risk modifier for malignancies occurring on a background of BRCA1 mutations. In addition, we were able to show that the site of the BRCA1 mutation does not influence the effect of the RAD51 C allele, indicating that this polymorphism contributes to prevention of disease in BRCA1 carriers. In conclusion, the RAD51 C allele seems to protect against both breast and ovarian cancer in women harboring BRCA1 mutations
    Type of Publication: Journal article published
    PubMed ID: 17301259
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  • 9
    Keywords: RECEPTOR ; CANCER ; CELLS ; CELL ; Germany ; RISK ; RISKS ; GENE ; GENOME ; ACTIVATED PROTEIN-KINASE ; ASSOCIATION ; polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; GLYCOPROTEIN ; NO ; IN-SITU ; SUBUNIT ; BRCA1 ; ovarian cancer ; OVARIAN-CANCER ; WOMEN ; MUTATION ; genetics ; PCR ; cancer risk ; MUTATIONS ; BETA ; ADHESION ; INTEGRIN ; SERIES ; RECEPTORS ; heredity ; REGRESSION ; RE ; INCREASE ; MUTATION CARRIERS ; HOMOZYGOSITY ; INTEGRINS ; case control studies ; analysis ; function ; INCREASED RISK ; odds ratio ; VARIABLES ; CANCER-RISK ; FRAGMENT ; OVARIAN ; FUNCTIONAL POLYMORPHISM ; INCREASES ; LOGISTIC-REGRESSION ; - ; OOPHORECTOMY ; ALPHA-V-BETA-3 ; PLATELET GLYCOPROTEIN-IIIA
    Abstract: Integrins are heterodimeric transmembrane glycoproteins that function as key adhesion and cell signalling receptors. A functional polymorphism in the integrin beta 3 subunit encoded by the ITGB3 gene, Leu33Pro, has been shown to modify a variety of traits of beta 3-expressing cells. To analyse the role of this functional polymorphism in modifying BRCA1-associated ovarian and breast cancer risks, a case - control study was performed among Polish BRCA1 mutation carriers including 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using PCR- based restriction fragment length polymorphism analysis. Odds ratios were calculated using univariate and multivariate logistic regression, taking into account a series of confounding variables, including the presence of related study subjects, that potentially could have biased any association. The results revealed that the ITGB3_ Leu33Pro polymorphism was associated with a 2.5- fold increased risk of ovarian cancer, whereas no association with breast cancer risk was found. Thus, it appears that the ITGB3_ Leu33Pro polymorphism may potentially increase the risk of ovarian cancer in Polish women with an inherited BRCA1 mutation
    Type of Publication: Journal article published
    PubMed ID: 17220212
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  • 10
    Keywords: CANCER ; carcinoma ; Germany ; CT ; DISEASE ; NEW-YORK ; RISK ; GENE ; GENOME ; PATIENT ; polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; IN-SITU ; BRCA1 ; ovarian cancer ; OVARIAN-CANCER ; WOMEN ; MUTATION ; PCR ; cancer risk ; REGION ; GENOTYPES ; HEREDITARY ; BREAST-CARCINOMA ; CARRIERS ; YOUNG ; ONCOLOGY ; case control study ; REGRESSION ; RE ; FAMILIES ; ALLELE ; INCREASE ; PENETRANCE ; TRANSITION ; MUTATION CARRIERS ; case control studies ; analysis ; SUPPRESSOR ; GENOTYPE ; breast carcinoma ; USA ; function ; female ; INCREASED RISK ; odds ratio ; CANCER-RISK ; inherited mutations ; OVARIAN ; HEREDITARY BREAST ; ENVIRONMENTAL-FACTORS ; INCREASES ; LOGISTIC-REGRESSION ; - ; BRCA1 carriers ; OOPHORECTOMY ; BILATERAL PROPHYLACTIC MASTECTOMY ; hereditary breast cancer ; prohibitin 3 ' untranslated region polymorphism ; risk modifier ; UNTRANSLATED REGION
    Abstract: The variable penetrance of breast cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. The C to T transition in the 3 ' untranslated region of the prohibitin ( PHB) gene alters mRNA function and has been shown to be associated with an increased breast cancer risk among young North- American women who have one first- degree relative with breast cancer. To investigate whether the PHB 3 ' UTR polymorphism acts as a modifier of hereditary breast cancer risk we performed a case- control study among female BRCA1 mutation carriers, which included 258 cases and 258 controls who were unaffected by ovarian cancer, in situ breast carcinoma or any other type of cancer. Controls were matched to cases by year of birth and BRCA1 mutation ( 5382insC, 300 T 〉 G, 4153delA). Genotyping analysis was performed using RFLP- PCR. Odds ratios ( OR) were calculated using conditional and penalised univariable and multivariable logistic regression. Multivariable penalised logistic regression revealed CT ( ORadj, 2.03; 95% CI, 1.17 - 3.59) and combined CT + TT ( ORadj, 2.12; 95% CI, 1.23 - 3.70) genotypes as significant modifiers of breast cancer risk. Breast cancer risk did not differ between carriers of the 300 T 〉 G and 5382insC mutation. Our results suggest that the PHB 3 ' UTR T allele increases the risk of breast cancer in patients who are already at increased risk of disease
    Type of Publication: Journal article published
    PubMed ID: 17004108
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