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  • 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
    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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  • 3
    Keywords: SUSCEPTIBILITY
    Abstract: BACKGROUND: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. METHODS: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. RESULTS: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. CONCLUSIONS: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987-. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 23513043
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  • 4
    Keywords: ASSOCIATION ; POLYMORPHISMS ; VARIANTS ; IDENTIFICATION ; METAANALYSIS ; LOCUS
    Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 x 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 x 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 x 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 x 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 x 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
    Type of Publication: Journal article published
    PubMed ID: 24764580
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  • 5
    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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  • 6
    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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  • 7
    Keywords: CANCER ; Germany ; NEW-YORK ; RISK ; RISKS ; GENE ; GENOME ; METABOLISM ; DNA ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; IN-SITU ; DECREASE ; ovarian cancer ; OVARIAN-CANCER ; WOMEN ; MUTATION ; etiology ; DNA methylation ; cancer risk ; COLON-CANCER ; MULTIVARIATE ; POLYMERASE-CHAIN-REACTION ; CARRIERS ; SERIES ; CHAIN-REACTION ; GASTRIC-CANCER ; METHYLATION ; BRCA2 MUTATIONS ; CHAIN ; ONCOLOGY ; REGRESSION ; RE ; polymerase chain reaction ; MUTATION CARRIERS ; METHYLENETETRAHYDROFOLATE REDUCTASE ; MTHFR ; ENZYME ; analysis ; USA ; C677T POLYMORPHISM ; DIETARY-FOLATE INTAKE ; HAPLOTYPE RECONSTRUCTION ; INCREASED RISK ; odds ratio ; VARIABLES ; CANCER-RISK ; FRAGMENT ; OVARIAN ; FUNCTIONAL POLYMORPHISM ; hereditary breast/ovarian cancer ; LOGISTIC-REGRESSION ; DNA-METHYLATION ; BRCA1 carriers ; risk modifier ; GENOMIC DNA HYPOMETHYLATION ; MTHFR POLYMORPHISMS ; Polish population
    Abstract: Methylenetetrahydrofolate reductase ( MTHFR), a key regulatory enzyme in the metabolism of folate, is suspected to play a role in the etiology of cancer, via its effects on DNA methylation and nucleotide synthesis. In this study we have investigated the effect of two functional polymorphisms of the MTHFR gene, MTHFR_ 677_ C 〉 T and MTHFR_ 1298_ A 〉 C, on breast and ovarian cancer risk in PolishBRCA1 mutation carriers. The study included 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 polymerase chain reaction followed by restriction fragment length polymorphism analysis. Odds ratios (OR) were calculated using univariate and multivariate logistic regression taking into account a series of confounding variables that potentially could have biased any association. The results revealed that the MTHFR _ 677_ C 〉 T change was associated with an increased risk of breast and ovarian cancer. The MTHFR_ 1298_ A 〉 C polymorphism was only associated with a decrease in breast cancer risk. Together, it appears that functional polymorphisms in the MTHFR gene modify the risk of breast and may potentially alter the risk of ovarian cancer in women with an inherited predisposition
    Type of Publication: Journal article published
    PubMed ID: 17063264
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  • 8
    Keywords: carcinoma ; fibroblasts ; METAANALYSIS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; REVERSE-TRANSCRIPTASE HTERT ; GENETIC-VARIATION ; COMMON VARIANTS ; TERT-CLPTM1L LOCUS ; BUCCAL CELLS
    Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
    Type of Publication: Journal article published
    PubMed ID: 23535731
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  • 9
    Keywords: RISK ; ASSOCIATION ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; statistics ; inflammation ; CARD11 ; FAMILY MEMBERS ; BCL10
    Abstract: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-kappaB (NF-kappaB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-kappaB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P 〈 2.5 x 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 x 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 x 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 x 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 x 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
    Type of Publication: Journal article published
    PubMed ID: 24740199
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  • 10
    Abstract: BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.
    Type of Publication: Journal article published
    PubMed ID: 27401727
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