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Sökning: WFRF:(Castelao JE)

  • Resultat 1-10 av 29
  • [1]23Nästa
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  • Michailidou, Kyriaki, et al. (författare)
  • Association analysis identifies 65 new breast cancer risk loci.
  • 2017
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 551:7678, s. 92-94
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
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  • Shu, Xiang, et al. (författare)
  • Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
  • 2019
  • Ingår i: ; 48:3, s. 795-806
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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  • Liu, Jingjing, et al. (författare)
  • Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk
  • 2020
  • Ingår i: ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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  • Schmit, Stephanie L, et al. (författare)
  • Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
  • 2018
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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  • Ali, Alaa M. G., et al. (författare)
  • Alcohol Consumption and Survival after a Breast Cancer Diagnosis: A Literature-Based Meta-analysis and Collaborative Analysis of Data for 29,239 Cases
  • 2014
  • Ingår i: Cancer Epidemiology Biomarkers & Prevention. - : American Association for Cancer Research. - 1538-7755 .- 1055-9965. ; 23:6, s. 934-945
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Evidence for an association of alcohol consumption with prognosis after a diagnosis of breast cancer has been inconsistent. We have reviewed and summarized the published evidence and evaluated the association using individual patient data from multiple case cohorts. Methods: A MEDLINE search to identify studies published up to January 2013 was performed. We combined published estimates of survival time for "moderate drinkers" versus nondrinkers. An analysis of individual participant data using Cox regression was carried out using data from 11 case cohorts. Results: We identified 11 published studies suitable for inclusion in the meta-analysis. Moderate postdiagnosis alcohol consumption was not associated with overall survival [HR, 0.95; 95% confidence interval (CI), 0.85-1.05], but there was some evidence of better survival associated with prediagnosis consumption (HR, 0.80; 95% CI, 0.73-0.88). Individual data on alcohol consumption for 29,239 cases with 4,839 deaths were available from the 11 case cohorts, all of which had data on estrogen receptor (ER) status. For women with ER-positive disease, there was little evidence that pre-or postdiagnosis alcohol consumption is associated with breast cancer-specific mortality, with some evidence of a negative association with all-cause mortality. On the basis of a single study, moderate postdiagnosis alcohol intake was associated with a small reduction in breast cancer-specific mortality for women with ER-negative disease. There was no association with prediagnosis intake for women with ER-negative disease. Conclusion: There was little evidence that pre- or post-diagnosis alcohol consumption is associated with breast cancer-specific mortality for women with ER-positive disease. There was weak evidence that moderate post-diagnosis alcohol intake is associated with a small reduction in breast cancer-specific mortality in ER-negative disease. Impact: Considering the totality of the evidence, moderate postdiagnosis alcohol consumption is unlikely to have a major adverse effect on the survival of women with breast cancer. (C) 2014 AACR.
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  • Archambault, Alexi N., et al. (författare)
  • Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
  • 2020
  • Ingår i: ; 158:5, s. 1274-
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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10.
  • Dadaev, Tokhir, et al. (författare)
  • Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.
  • 2018
  • Ingår i: ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
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