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  • 1
    Keywords: PROSTATE ; prevention ; WOMEN ; SUBTYPES ; FAMILY-HISTORY ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONSORTIUM
    Abstract: BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
    Type of Publication: Journal article published
    PubMed ID: 25855707
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  • 2
    Keywords: carcinoma ; WOMEN ; PROSTATE-CANCER ; CLINICAL-SIGNIFICANCE ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; COHORT CONSORTIUM ; IDENTIFIES 2
    Abstract: INTRODUCTION: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS. METHODS: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile. RESULTS: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons 〈0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies. CONCLUSIONS: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.
    Type of Publication: Journal article published
    PubMed ID: 26070784
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  • 3
    Keywords: polymorphism ; TUMOR-SUPPRESSOR GENE ; mammographic density ; MULTIETHNIC COHORT ; BASE-LINE CHARACTERISTICS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; IDENTIFIES 2
    Abstract: The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over-all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta-analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1-rs3817198 was significantly associated with improved OS (HRper-allele =0.70; 95% CI: 0.58-0.85; ptrend = 2.84 x 10-4 ; HRheterozygotes = 0.71; 95% CI: 0.55-0.92; HRhomozygotes = 0.48; 95% CI: 0.31-0.76; p2DF = 1.45 x 10-3 ). In silico, the C allele of LSP1-rs3817198 was predicted to increase expression of the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C). In the meta-analysis, TNRC9-rs3803662 was significantly associated with increased death hazard (HRMETA =1.09; 95% CI: 1.04-1.15; ptrend = 6.6 x 10-4 ; HRheterozygotes = 0.96 95% CI: 0.90-1.03; HRhomozygotes = 1.21; 95% CI: 1.09-1.35; p2DF =1.25 x 10-4 ). In conclusion, we show that there is little overlap between the breast cancer risk single nucleotide polymorphisms (SNPs) identified so far and the SNPs associated with breast cancer prognosis, with the possible exceptions of LSP1-rs3817198 and TNRC9-rs3803662.
    Type of Publication: Journal article published
    PubMed ID: 25611573
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  • 4
    Keywords: CANCER ; RISK ; PROSTATE-CANCER ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; IDENTIFIES 5
    Abstract: Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (〈50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
    Type of Publication: Journal article published
    PubMed ID: 22037553
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  • 5
    Keywords: POLYMORPHISMS ; VARIANTS ; prevention ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; D-BINDING PROTEIN
    Abstract: BACKGROUND: Studies suggest that vitamin D status may be associated with prostate cancer risk although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D [25(OH)D] status. We examined prostate cancer risk in relation to single-nucleotide polymorphisms (SNP) in four genes shown to predict circulating levels of 25(OH)D. METHODS: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the National Cancer Institute (NCI) Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer. RESULTS: We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D [per A allele, OR, 0.86; 95% confidence interval (CI), 0.80-0.93; Ptrend = 0.0002) but an increased risk for nonaggressive disease (per A allele: OR, 1.10; 95% CI, 1.04-1.17; Ptrend = 0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6-8 vs. 0-1 alleles, 0.66; 95% CI, 0.44-0.98; Ptrend = 0.003). CONCLUSIONS: In this large, pooled analysis, genetic variants related to lower 25(OH)D levels were associated with a decreased risk of aggressive prostate cancer. IMPACT: Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 23377224
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  • 6
    Keywords: DISEASES ; VARIANTS ; IDENTIFICATION ; COLORECTAL-CANCER ; METAANALYSIS ; susceptibility loci ; CHALLENGES ; Consortia ; ASSOCIATION SCAN ; SARCOSINE
    Abstract: Background: No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS). Objective: To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer. Design, setting, and participants: SNPs implicated in any phenotype other than prostate cancer (p 〈= 10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24 534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Outcome measurements and statistical analysis: Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated. Results and limitations: A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p = 1.6 x 10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p = 3.22 x 10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p = 2.5 x 10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p = 4.67 x 10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL. Conclusions: We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology. Patient summary: We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified.
    Type of Publication: Journal article published
    PubMed ID: 25277271
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  • 7
    Keywords: GENES ; METAANALYSIS ; GROWTH-FACTOR-I ; BINDING PROTEIN-3 ; 8Q24 ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; SEQUENCE VARIANTS ; MULTIPLE ; PSA LEVELS
    Abstract: Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10(-28)). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade,8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined
    Type of Publication: Journal article published
    PubMed ID: 21390317
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  • 8
    Keywords: COHORT ; DNA ; ASSOCIATION ; breast cancer ; BREAST-CANCER ; WOMEN ; HORMONE REPLACEMENT THERAPY ; smoking ; prostate cancer ; cancer risk ; VALIDITY ; ALCOHOL ; ALCOHOL-CONSUMPTION ; ALLELES ; BASE-LINE CHARACTERISTICS ; progesterone receptor ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; Breast cancer risk factors ; AMERICAN ; FGFR2 GENE
    Abstract: Background Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. Methods To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 x 10(-4)) was done. Casecase comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. Results We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 x 10(-3) -3.96 x 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). Conclusion This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer
    Type of Publication: Journal article published
    PubMed ID: 21791674
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  • 9
    Keywords: CANCER ; RISK ; SUSCEPTIBILITY ; HEIGHT ; susceptibility loci ; SEQUENCE VARIANTS ; FGF10
    Abstract: Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 x 10(-8) to P = 2.7 x 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining similar to 25% of the familial risk in this disease, have now been identified
    Type of Publication: Journal article published
    PubMed ID: 21743467
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  • 10
    Keywords: MODELS ; COHORT ; PROSTATE-CANCER ; ESTROGEN ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; BASE-LINE CHARACTERISTICS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS
    Abstract: OBJECTIVE: There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumours with different hormone receptor status. MATERIAL AND METHODS: Within the Breast and Prostate Cancer Cohort Consortium, we analysed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age adjusted and cohort-adjusted concordance statistic (AUROC(a)). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement was used to measure improvements in risk prediction. RESULTS: We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROC(a) going from 2.7% to 4%). Discriminatory ability for all models varied strongly by hormone receptor status. DISCUSSION AND CONCLUSIONS: Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor-positive cases, but the gain in discriminatory quality is not sufficient for clinical application.
    Type of Publication: Journal article published
    PubMed ID: 22972951
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