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  • 1
    Abstract: Polymorphisms in genes involved in DNA repair, steroid hormone biosynthesis/metabolism/signaling, folate metabolism as well as cell growth are prime candidates for possible associations with breast and ovarian cancer risk in women with an inherited predisposition. We investigated 29 polymorphisms in 20 genes encoding key proteins of the above four biological pathways for their breast and ovarian cancer risk modifying effect in Polish women harboring BRCA1 founder mutations. Of the analyzed genes, ERCC2, XRCC1, XRCC2, XRCC3 and Lig4 participate in DNA repair, TP53 in cell cycle check point control, AIB1, AR, COMT, CYP11A1, CYP17A1, CYP19A1, HSD17 and PGR in steroid hormone biosynthesis/metabolism/signaling, TYMS in folate metabolism and HER2, IL6, LRP1, TGFB and TGFBR1 affect cell growth. Using validated methods, we genotyped 319 breast cancer cases, 146 ovarian cancer cases and 290 unaffected controls, all of whom harbored one of three causative mutations in BRCA1. Our results revealed no association of any of the investigated polymorphisms with BRCA1-associated breast or ovarian cancer risk. Thus, it appears that these polymorphisms do not influence disease risk in Polish women carrying one of the three common BRCA1 founder mutations.
    Type of Publication: Journal article published
    PubMed ID: 19360465
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  • 2
    Keywords: GENE ; NF-KAPPA-B ; MUTATIONS ; CENTRAL-NERVOUS-SYSTEM ; medulloblastoma ; SUBGROUPS ; GLIOBLASTOMA ; CHILDHOOD EPENDYMOMAS ; PEDIATRIC INTRACRANIAL EPENDYMOMAS ; POSTERIOR-FOSSA EPENDYMOMAS
    Abstract: Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
    Type of Publication: Journal article published
    PubMed ID: 25965575
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  • 3
    Keywords: CANCER ; EXPRESSION ; tumor ; Germany ; MODEL ; MODELS ; SYSTEM ; HISTORY ; RISK ; GENE ; GENES ; PROTEIN ; PROTEINS ; TUMORS ; FAMILY ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; TARGET ; TRANSCRIPTIONAL ACTIVITY ; ovarian cancer ; OVARIAN-CANCER ; WOMEN ; p53 ; REGION ; GENOTYPES ; CELL-GROWTH ; ONCOLOGY ; REGRESSION ; ASSOCIATIONS ; VARIANT ; development ; HAPLOTYPE ; FAMILY-HISTORY ; INCREASED RISK ; population-based ; GENETIC-VARIATION ; breast cancer risk ; ESTROGEN-RECEPTOR-ALPHA ; MULTIPLE IMPUTATION ; SUMOYLATION ; Genetic ; tumor grade ; UBC9 and PIAS3 polymorphisms
    Abstract: SUMOylation consists in the covalent conjugation of small ubiquitin-related modifiers to target proteins. SUMOylation participates in processes that are tightly linked to tumorigenesis, and genetic variability in the SUMO-conjugating system may influence the development of breast cancer. We recently reported that variation in the UBC9 gene encoding the SUMO-conjugating enzyme may affect the grade of breast tumors. Following comprehensive in silico analyses for detection of putative functional polymorphisms in 14 genes of the SUMO system, we selected one coding SNP in PIAS3 and seven tag SNPs in UBC9 for association analyses. Results were based on 1,021 cases, and 1,015 matched controls from the population-based GENICA study. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by conditional logistic regression. To explore the association with polymorphisms closely linked to the genotyped variants, multiple imputation based on HapMap data was applied. The study revealed associations of four UBC9 polymorphisms with risk of grade 1 tumors. Comparison of genotype and haplotype models indicated that the best representation of risk solely relied on rs7187167 under dominant penetrance. Women carrying the rare allele showed an increased risk of grade 1 tumors compared with common homozygotes (OR 1.87, 95% CI 1.18-2.95). This effect appeared to be stronger in women with a family history of breast or ovarian cancer. Imputation of polymorphisms in a 300-kb region around the genotyped polymorphisms identified no variants with stronger associations. Our findings suggest that genetic variation in UBC9 may affect the risk of grade 1 breast tumors
    Type of Publication: Journal article published
    PubMed ID: 19760037
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  • 4
    Keywords: CANCER ; COMBINATION ; PATHWAY ; PATHWAYS ; incidence ; RISK ; GENE ; GENES ; METABOLISM ; RISK-FACTORS ; BIOMARKERS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; DELETION ; hormone ; WOMEN ; risk factors ; RISK FACTOR ; LENGTH ; ESTROGEN METABOLISM ; ENDOMETRIAL CANCER ; 2-methoxyestradiol ; ESTRADIOL ; ONCOLOGY ; VARIANT ; ESTROGEN ; ALLELES ; biomarker ; methods ; GENOTYPE ; HAPLOTYPE ; ANDROGEN RECEPTOR ; HORMONES ; PERSPECTIVES ; INCREASED RISK ; CANCER-RISK ; ESTROGEN-RECEPTOR-ALPHA ; Genetic ; hypothesis ; AREA ; Repeat length ; GSTs ; CYTOCHROME P4501B1 ; Steroidogenesis
    Abstract: Objectives: The incidence of endometrial cancer has recently increased substantially and studies have shown that altered levels of exogenous and endogenous hormones are associated with individual variation in endometrial cancer risk. The environmental and reproductive risk factors that influence these hormones are well known, however, genetic variants involved in hormone biosynthesis and estrogen metabolism have not been well established in endometrial cancer. Methods: To determine whether polymorphisms in genes of the steroid hormone biosynthesis and metabolism pathways are associated with endometrial cancer risk, 28 polymorphisms in 18 genes were genotyped in 191 endometrial cancer cases and 291 healthy controls. Results: The GSTM1 deletion and the variant (GG) genotype of the CYP1B1 rs1800440 polymorphism were associated with a decreased risk of developing endometrial cancer. Furthermore, combinations of haplotypes in CYP1A1, CYP1B1 and GSTs were associated with a decreased risk. The analysis of the repeat polymorphisms revealed that women with the long repeat allele length of the ESR1 (GT)n repeat polymorphism were at an increased risk of developing endometrial cancer. Conversely, women with two long repeat length alleles of the (CAG)n repeat polymorphism in the AR correlated with a decrease in endometrial cancer risk compared to women with one or two alleles with the short repeat length. Conclusions: The findings are consistent with our hypothesis that variability in genes involved in steroidogenesis and estrogen metabolism may alter the risk of developing endometrial cancer, suggesting that they may be useful as biomarkers for genetic susceptibility to endometrial cancer. (c) 2010 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20381444
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  • 5
    Keywords: EXPRESSION ; DISEASE ; PROTEIN ; Drosophila ; EVOLUTION ; LOCALIZATION ; SNPs ; HAPLOTYPE
    Abstract: The human homolog of the Drosophila Scribble (SCRIB) tumor suppressor gene encodes a protein that regulates apical-basolateral polarity in mammalian epithelia and controls cell proliferation. Due to the role of cell polarity proteins in human cancers, we investigated whether genetic variability in SCRIB impacts breast carcinogenesis and tumor pathology. Five genetic variants were analyzed for an association with breast cancer risk and histopathological tumor parameters using a single nucleotide polymorphism (SNP) tagging approach. Genotyping of five tag SNPs was performed by TaqMan allelic discrimination and RFLP-based PCR using the GENICA population-based breast cancer case-control collection including 1,021 cases and 1,015 age-matched controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by ordinal logistic regression. None of the tag SNPs was associated with breast cancer risk or tumor characteristics. Our findings suggest that genetic variability in the SCRIB polarity gene does not contribute to breast cancer development.
    Type of Publication: Journal article published
    PubMed ID: 20936341
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  • 6
    Keywords: CANCER ; EXPRESSION ; GROWTH ; proliferation ; carcinoma ; CELL ; COMBINATION ; SUPPORT ; HISTORY ; POPULATION ; RISK ; GENE ; PATIENT ; COMPLEX ; COMPLEXES ; FAMILY ; RISK-FACTORS ; CARCINOGENESIS ; cell cycle ; CELL-CYCLE ; MEMBERS ; polymorphism ; POLYMORPHISMS ; family history ; WOMEN ; colorectal cancer ; risk factors ; COLORECTAL-CANCER ; PCR ; cancer risk ; GENOTYPES ; CANCER-PATIENTS ; CANCER PATIENTS ; OVEREXPRESSION ; NONPOLYPOSIS COLORECTAL-CANCER ; CYCLIN D1 ; ONCOLOGY ; REGRESSION ; RE ; FAMILIES ; VARIANT ; ESTROGEN ; analysis ; methods ; PHASE ; GENOTYPE ; FAMILY-HISTORY ; RISK-FACTOR ; CANCERS ; CANCER-RISK ; ENGLAND ; comparison ; AGE-OF-ONSET ; CELL-CYCLE REGULATORS ; D1 POLYMORPHISM ; DERAILMENT ; FAMILY-MEMBERS
    Abstract: Background: Cyclin D1 is integral for the G1 to S phase of the cell cycle as it regulates cellular proliferation. A polymorphism in cyclin D1, 870 G〉A, causes overexpression and supports uncontrollable cellular growth. This polymorphism has been associated with an increased risk of developing many cancers, including endometrial cancer. Methods: The 870 G〉A polymorphisms (rs605965) in the cyclin D1 gene was genotyped in an Australian endometrial cancer case-control population including 191 cases and 291 controls using real-time PCR analysis. Genotype analysis was performed using chi-squared (chi(2)) statistics and odds ratios were calculated using unconditional logistic regression, adjusting for potential endometrial cancer risk factors. Results: Women homozygous for the variant cyclin D1 870 AA genotype showed a trend for an increased risk of developing endometrial cancer compared to those with the wild-type GG genotype, however this result was not statistically significant (OR 1.692 95% CI (0.939-3.049), p = 0.080). Moreover, the 870 G〉A polymorphism was significantly associated with family history of colorectal cancer. Endometrial cancer patients with the homozygous variant AA genotype had a higher frequency of family members with colorectal cancer in comparison to endometrial cancer patients with the GG and combination of GG and GA genotypes (GG versus AA; OR 2.951, 95% CI (1.026-8.491), p = 0.045, and GG+GA versus AA; OR 2.265, 95% CI (1.048-4.894), p = 0.038, respectively). Conclusion: These results suggest that the cyclin D1 870 G〉A polymorphism is possibly involved in the development of endometrial cancer. A more complex relationship was observed between this polymorphism and familial colorectal cancer
    Type of Publication: Journal article published
    PubMed ID: 18822177
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  • 7
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; carcinoma ; CELL ; COMBINATION ; HISTORY ; RISK ; GENE ; GENES ; ACCUMULATION ; FAMILY ; cell cycle ; CELL-CYCLE ; CYCLE ; MEMBERS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; COLORECTAL-CANCER ; inactivation ; PCR ; cancer risk ; GENOTYPES ; MDM2 ; OVEREXPRESSION ; CYCLE CONTROL ; ENDOMETRIAL CANCER ; P53 MUTATIONS ; TP53 ; FAMILIES ; VARIANT ; DETERMINANTS ; development ; GENOTYPE ; CYCLE ARREST ; FAMILY-HISTORY ; USA ; CANCER-RISK ; ERROR ; GERMLINE POLYMORPHISM
    Abstract: Objectives. Determinants of endometrial cancer grade have not been precisely defined, however, cell cycle control is considered to be integrally involved in endometrial cancer development. TP53 and MDM2 are essential components for cell cycle arrest and apoptosis. Polymorphisms in these genes cause TP53 inactivation and MDM2 over-expression, leading to accumulation of genetic errors. Methods. One polymorphism in MDM2, rs2279744 (SNP309) and three polymorphisms in TP53 rs1042522 (R72P), rs17878362 and rs1625895 were genotyped in 191 endometrial cancer cases and 291 controls using PCR-based fragment analysis, RFLP analysis and real-time PCR. Results. The results showed no associations of the three TP53 polymorphisms and MDM2 SNP309 alone or in combination with endometrial cancer risk. However, the combination of MDM2 SNP309 and the three TP53 polymorphisms was significantly associated with a higher grade of endometrial cancer (wild-type genotypes versus variant genotypes: OR 4.15, 95% CI 1.82-9.46, p=0.0003). Analysis of family history of breast cancer revealed that the variant genotypes of the three TP53 polymorphisms were significantly related to a higher frequency of family members with breast cancer in comparison to endometrial cancer cases without a family history of breast cancer (wild-type genotypes versus variant genotypes: OR 2.78, 95% CI 1.3 6-5.67, p = 0.004). Conclusions. The combination of the MDM2 SNP309 and the three TP53 polymorphisms appear to be related to a higher grade of endometrial cancer. The association of the endometrial cancer cases with family history of breast cancer and the three TP53 polymorphisms suggests that this constellation of malignancies may represent a low-risk familial cancer grouping. (C) 2009 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19193430
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  • 8
    Keywords: RECEPTOR ; CANCER ; SURVIVAL ; MODEL ; DIAGNOSIS ; DISEASE ; POPULATION ; RISK ; GENE ; GENES ; PATIENT ; RISK-FACTORS ; CARCINOGENESIS ; mechanisms ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; BREAST-CANCER ; PROGRESSION ; AGE ; WOMEN ; SNP ; PATHOGENESIS ; PCR ; cancer risk ; RISK FACTOR ; REGION ; LENGTH ; POPULATIONS ; INVOLVEMENT ; RECEPTORS ; ENDOMETRIAL CANCER ; SINGLE ; REGRESSION ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; development ; ESTROGEN ; ALLELES ; GENOTYPE ; HAPLOTYPES ; GENDER ; TESTS ; POWER ; survival analysis ; estrogen receptor ; pharmacology ; USA ; INCREASED RISK ; RISK-FACTOR ; CANCER-RISK ; VARIANT ALLELES ; CANCER GENETICS ; Haplotype analysis ; Genetic ; ALPHA GENE ; BETA ESR2 POLYMORPHISMS ; estrogen receptors ; RESTRICTION ; SELECTIVE LIGANDS
    Abstract: There is evidence that estrogens and some of their metabolites are involved in endometrial cancer pathogenesis. As estrogens mediate their effects via the estrogen receptors, ESR1 and ESR2, the objective of this investigation was to determine whether six single nucleotide polymorphisms (SNPs) in these two genes were over-represented in a population of endometrial cancer patients compared with a healthy matched control population, thereby associating differences in these genes with endometrial cancer. The study is a case-control investigation large enough to detect a two-fold increased risk, assuming a dominant genetic model, with P = 0.05 and 80% power. The study and control populations were all from the Hunter-New England region of New South Wales, Australia collected between the years 1992 and 2005. The study consisted of 191 endometrial cancer patients and 291 healthy controls matched for gender and age. Two SNPs in ESR1 and four SNPs in ESR2 were genotyped using PCR-based restriction fragment length polymorphism analysis and real-time PCR. Odds ratios were calculated using unconditional logistic regression and SIMHAP was used for haplotype analysis, adjusting for potential endometrial cancer risk factors. Kaplan-Meier survival analysis, Cox regression and t tests were used to examine the patient's age of diagnosis of endometrial cancer and genotype. Over-representation of ESR1 and ESR2 polymorphisms in the endometrial cancer population compared with the control population indicates an involvement in the development and/or progression of disease. Two ESR1 (rs2234693 and rs9340799) and two ESR2 (rs1255998 and rs944050) polymorphisms were associated with an increased risk of endometrial cancer. Following adjustment for risk factors, the association with the ESR1 and ESR2 polymorphisms (rs2234693, rs1255998 and rs944050) remained highly significant. Haplotype analysis revealed that carriers of the ESR1 haplotype (variant alleles; rs2234693 and rs9340799) and the ESR2 haplotype (variant allele; rs1255998 and wild-type alleles; rs944050, rs4986938 and rs1256049) were at an increased risk (OR 1.862, P = 0.013 and OR 1.918, P = 0.046 respectively). This risk was even greater in women carrying both risk haplotypes (OR 5.041, P = 0.007). Our data suggest that the ESR1 (rs2234693 and rs9340799) and the ESR2 (rs1255998 and rs944050) polymorphisms may be associated with an increased risk of developing endometrial cancer
    Type of Publication: Journal article published
    PubMed ID: 19438492
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  • 9
  • 10
    Keywords: CANCER ; Germany ; PATHWAY ; PATHWAYS ; NEW-YORK ; RISK ; GENE ; GENES ; PROTEIN ; PROTEINS ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; NO ; mass spectrometry ; PCR ; MASS-SPECTROMETRY ; case-control studies ; ESTROGEN METABOLISM ; BRCA2 MUTATIONS ; CLUSTER ; POSTMENOPAUSAL WOMEN ; ONCOLOGY ; case-control study ; REGRESSION ; RE ; CATECHOL-O-METHYLTRANSFERASE ; HORMONE-REPLACEMENT THERAPY ; ESTROGEN ; analysis ; USA ; HAPLOTYPE RECONSTRUCTION ; CANDIDATE ; CANCER-RISK ; FRAGMENT ; COMT ; association analyses ; MULTIFACTOR-DIMENSIONALITY REDUCTION ; multivariate analyses
    Abstract: Polymorphisms within the estrogen metabolic pathway are prime candidates for a possible association with breast cancer risk. We investigated 11 genes encoding key proteins of this pathway for their potential contribution to breast cancer risk. Of these CYP17A1, CYP19A1, EPHX1, HSD17B1, SRD5A2, and PPARG2 participate in biosynthesis, CYP1A1, CYP1B1, COMT, GSTP1, and SOD2 in catabolism and detoxification. We performed a population-based case-control study with 688 incident breast cancer cases and 724 controls from Germany and genotyped 18 polymorphisms by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), PCR based RFLP (restriction fragment length polymorphism), and TaqMan (R) allelic discrimination. Genotype frequencies were compared between cases and controls and odds ratios were calculated by conditional logistic regression. Further statistical analyses were based on cluster analysis, multifactor dimensionality reduction, logic regression, and global testing. Single factor analyses pointed to CYP1B1_1294_GG as a possible breast cancer risk modulator (OR = 2.57; 95% CI: 1.34-4.93) and two way stratification suggested associations between BMI 〉= 30 kg/m(2) and COMT_472_GG (P = 0.0076 and P = 0.0026), BMI 〈 20 kg/m(2) and HSD17B1_937_GG (P = 0.0082) as well as CYP17A1_-34_CC and HRT use 〉= 10 years (P = 0.0063). Following correction for multiple testing none of these associations remained significant. No significant association between breast cancer risk and genetic polymorphisms was observed in multifactor analyses. The tested polymorphisms of the estrogen metabolic pathway may not play a direct role in breast cancer risk. Therefore, future association studies should be extended to other polymorphisms and other regulatory pathways
    Type of Publication: Journal article published
    PubMed ID: 17588204
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