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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: 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
    Abstract: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
    Type of Publication: Journal article published
    PubMed ID: 22253144
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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 ; 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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  • 8
    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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  • 9
    Keywords: COMPLEX ; OVARIAN-CANCER ; ESTROGEN-RECEPTOR ; ALLELES ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; NONSENSE ; 2Q35
    Abstract: Abstract: Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).
    Type of Publication: Journal article published
    PubMed ID: 20852631
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  • 10
    Keywords: CANCER ; EXPRESSION ; RISK ; GENE ; SUSCEPTIBILITY ; breast cancer ; PATTERNS ; risk factors ; ESTROGEN-RECEPTOR ; ALLELES ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; PROGESTERONE-RECEPTOR ; BRCA2 MUTATION CARRIERS ; Risk prediction
    Abstract: Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P 〈= 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P 〈= 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment
    Type of Publication: Journal article published
    PubMed ID: 21596841
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