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  • CANCER  (5)
  • BREAST  (4)
  • VARIANTS  (4)
  • 1
    Keywords: CANCER ; COHORT ; POPULATION ; RISK ; GENE ; GENES ; ASSOCIATION ; POLYMORPHISMS ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; OVARIAN-CANCER ; EXCISION-REPAIR ; ONCOLOGY ; BRCA2 ; breast cancer risk ; NUCLEOTIDE ; ERCC4
    Abstract: BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
    Type of Publication: Journal article published
    PubMed ID: 19920816
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  • 2
    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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  • 3
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; Germany ; THERAPY ; POPULATION ; RISK ; SITES ; GENE ; GENES ; HYBRIDIZATION ; PROTEIN ; MESSENGER-RNA ; CARCINOGENESIS ; BINDING ; DOWN-REGULATION ; TYROSINE KINASE INHIBITOR ; ASSOCIATION ; polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; WOMEN ; TUMOR PROGRESSION ; SNP ; TARGETS ; REPRESSION ; RETINOIC ACID ; VARIANT ; THERAPIES ; SINGLE NUCLEOTIDE POLYMORPHISMS ; BINDING-SITES ; CONFER SUSCEPTIBILITY ; therapeutic ; COMMON VARIANTS ; CHROMOSOME 6Q ; II RECEPTOR
    Abstract: MicroRNAs (miRNAs) negatively regulate expression of target transcripts by hybridization to complementary sites of their messenger RNA targets. Chen et al. have described several putative functional single nucleotide polymorphisms (SNPs) in miRNA target sites. Here, we selected 11 miRNA target site SNPs located in 3' untranslated regions of genes involved in cancer and breast cancer to analyze their impact on breast cancer risk using a large familial study population. Whereas no association was observed for 10 SNPs, a significant association was revealed for the variant affecting a miRNA target site in the estrogen receptor (ESR) 1. Age stratification showed that the association was stronger in premenopausal women [C versus T: odds ratio (OR) = 0.60, confidence interval (CI) = 0.41-0.89, P = 0.010]. Furthermore, the effect was stronger in high-risk familial cases (C versus T: OR = 0.42, CI = 0.25-0.71, P = 0.0009). Clinical studies have shown that elimination of ESR1 significantly reduces breast cancer risk. Thus, therapies that inhibit ESR1 are used for breast cancer treatment. According to in silico analysis, ESR1_rs2747648 affects the binding capacity of miR-453, which is stronger when the C allele is present. In contrast, the T allele attenuates the binding of miR-453, which might lead to a reduced miRNA-mediated ESR1 repression, in consequence higher ESR1 protein levels and an increased breast cancer risk. Thus, the breast cancer protective effect observed for the C allele in premenopausal women is biologically reasonable. The analysis of large study populations in multicentre collaboration will be needed to verify the association and answer questions regarding the possible impact of this variant on therapeutic and clinical outcome
    Type of Publication: Journal article published
    PubMed ID: 19028706
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  • 4
    Keywords: CANCER ; Germany ; DISEASE ; POPULATION ; RISK ; MESSENGER-RNA ; IMPACT ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; OVARIAN-CANCER ; MUTATION ; SNP ; cancer risk ; MUTATIONS ; US ; case-control studies ; BRCA1/2 ; case control study ; case-control study ; GENETIC EPIDEMIOLOGY ; BRCA2 ; VARIANT ; SNPs ; MUTATION CARRIERS ; USA ; CANCER-RISK ; NOV ; breast cancer risk ; BRCA1 and BRCA2 ; Codon-usage ; SILENT ; SYNONYMOUS SNP
    Abstract: Mutations in BRCA1 and BRCA2 are associated with increased breast cancer risk. While numerous non-synonymous SNPs in BRCA1/2 have been investigated for breast cancer risk, the impact of synonymous SNPs has not been studied so far. Recently, it has been reported that synonymous SNPs leading to an aberration from the preferred codon-usage can have functional effects and consequently be associated with disease. This motivated us to search for SNPs with the tendency to differential codon-usage in BRCA1/BRCA2. Based on defined criteria, two codon-usage-changing variants, Ser455Ser (1365A 〉 G) and Ser2414Ser (7242A 〉 G), were detected in BRCA2, whereas no such variant could be identified in BRCA1. We investigated the impact of these variants on breast cancer risk in a large case-control study. However, both SNPs, BRCA2 Ser2414Ser (7242A 〉 G) and Ser455Ser (1365A 〉 G), showed no association with breast cancer risk. This indicates that these codon-usage-changing SNPs have no major impact on familial breast cancer risk
    Type of Publication: Journal article published
    PubMed ID: 19229607
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  • 5
    Keywords: POPULATION ; RISK ; TUMORS ; ASSOCIATION ; VARIANTS ; breast cancer ; SELECTION ; SUBTYPES ; breast cancer risk ; CONSORTIUM ; INVESTIGATORS ; MODIFIERS ; COMMON VARIANTS ; GENETIC-VARIANTS ; SUSCEPTIBILITY ALLELES ; ZNF365
    Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers
    Type of Publication: Journal article published
    PubMed ID: 23544013
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  • 6
    Keywords: DISEASES ; SUSCEPTIBILITY ; VARIANTS ; OXIDATIVE STRESS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; OVARIAN ; CONSORTIUM ; MULTIPLE ; GENETIC MODIFIERS ; DNA HAPLOGROUPS
    Abstract: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
    Type of Publication: Journal article published
    PubMed ID: 25925750
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  • 7
    Keywords: CANCER ; EXPRESSION ; MODEL ; COMMON ; POPULATION ; RISK ; RISKS ; GENE ; PROTEIN ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; OVARIAN-CANCER ; MUTATION ; genetics ; SNP ; cancer risk ; CARRIERS ; case-control studies ; ESTROGEN-RECEPTOR ; SINGLE ; molecular biology ; case control study ; case-control study ; population-based case-control study ; BRCA2 ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; MUTATION CARRIERS ; ALLELES ; INCREASED RISK ; population-based ; CANCER-RISK ; COMMON VARIANT ; 8Q24 ; NOV ; GENOME-WIDE ASSOCIATION ; GENERAL-POPULATION ; breast cancer risk ; UK ; Genetic ; 33 ; COMMON VARIANTS ; Genome-wide association studies ; BRCA1 and BRCA2
    Abstract: Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not
    Type of Publication: Journal article published
    PubMed ID: 19656774
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