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- Dixon-Suen, Suzanne C, et al.
(författare)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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- Mueller, Stefanie H., et al.
(författare)
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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
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Ingår i: Genome Medicine. - : BioMed Central (BMC). - 1756-994X .- 1756-994X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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- Figlioli, G, et al.
(författare)
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FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women
- 2023
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 31:5, s. 578-587
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Tidskriftsartikel (refereegranskat)abstract
- Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07–2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08–1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
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- Escala-Garcia, M, et al.
(författare)
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Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 19787-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
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- Heinälä, M, et al.
(författare)
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Survey on European methodologies in the risk assessment of chemical exposures in emergency response situations
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Survey on European methodologies in the risk assessment of chemical exposures in emergency response situations. Prevention or mitigation of human health effects is often the major determinant underlying chemical incident prevention policy and emergency response decisions. The ability to perform a human health risk assessment is a prerequisite for effective chemical incident prevention, preparedness and response. To identify knowledge gaps, needs and concerns relating to health risks from chemical incidents, a web-based survey was sent to various groups of stakeholders. The release of acutely toxic substances and irritating/corrosive substances appeared to be the most important risk scenario. Almost 40% of the respondents also expected a future increase of chemical terrorism or sabotage. Developments in nanotechnology were perceived as potential future risk drivers although more information is needed on the health hazards of nanoparticles. A high number of respondents also expressed concern for the consequences of globalization, international trade and higher industry efficiency demands on health risks through chemical incidents. Acute Exposure Reference Values (AERVs) were considered important cornerstones but a need was expressed for recommendations on their use for the management of chemical emergencies. Based on this survey, it is advised to develop European consensus on an authoritative methodology to derive AERVs, to design a process for their implementation and to provide guidance and training on their practical application. Attention should be paid to the widely used acutely toxic and irritating/corrosive substances, to specific endpoints such as carcinogenicity and reproductive toxicity and new and emerging chemicals. Research should focus on developing plausible scenarios for emerging human health risks from chemical incidents to allow better prioritisation of future risk assessments.
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| 13. |
- Bos, Peter MJ, et al.
(författare)
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Human risk assessment of single exposure in chemical incidents : present situation and new and increasing chemical incident scenarios
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The release of chemicals from their containment, either accidentally or deliberately, is one of the most relevant risk scenarios in Europe. A human health risk assessment is a prerequisite for chemical incident prevention, preparedness and response. European guidance and harmonized Acute Exposure Reference Values (AERVs) are urgently needed for effective human health risk assessment in the context of chemical incidents.At present, no broad European consensus is available on guidance for risk assessment, risk management and risk communication purposes in case of chemical incidents. A review of legislation, existing or currently under revision, suggests that harmonized European guidance is not expected to be developed in the short term. An increasing number of European countries are developing their own procedures to assess the human health risk of chemical incident scenarios. The AERVs thus produced serve different purposes and are not interchangeable. Lack of international harmonization seriously obstructs a consistent response in chemical emergencies with transboundary effects within and beyond the EU, will hamper multinational companies attempting to make consistent risk assessments worldwide and will hinder consistent and transparent assessment, and management and communication of risks by different stakeholders.Emerging chemical incident risk scenarios and risk drivers have been identified. It is recommended to monitor more frequently at an early stage for new trends in chemicals, scenarios and risks from chemical incidents. A need for a specific approach to deal with single exposure to mixtures of chemicals is identified, as well as for specific guidance to adequately protect professional first responders.
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| 14. |
- Jiao, Xiang, et al.
(författare)
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PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
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Tidskriftsartikel (refereegranskat)abstract
- Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
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| 16. |
- Heinälä, Milla, et al.
(författare)
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Survey on methodologies in the risk assessment of chemical exposures in emergency response situations in Europe
- 2013
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Ingår i: Journal of Hazardous Materials. - : Elsevier. - 0304-3894 .- 1873-3336. ; 244, s. 545-554
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Tidskriftsartikel (refereegranskat)abstract
- A scientifically sound assessment of the risk to human health resulting from acute chemical releases is the cornerstone for chemical incident prevention, preparedness and response. Although the general methodology to identify acute toxicity of chemicals has not substantially changed in the last decades, there is ongoing debate on the current approaches for human health risk assessment in scenarios involving acute chemical releases.A survey was conducted to identify 1) the most important present and potential future chemical incident scenarios and anticipated changes in chemical incidents or their management; 2) information, tools and guidance used in different countries to assess health risks from acute chemical releases; and 3) needs for new information, tools, guidance and expertise to enable the valid and rapid health risk assessment of acute chemical exposures.According to the results, there is an obvious variability in risk assessment practices within Europe. The multiplicity of acute exposure reference values appears to result in variable practices. There is a need for training especially on the practical application of acute exposure reference values. Although acutely toxic and irritating/corrosive chemicals will remain serious risks also in future the development of plausible scenarios for potential emerging risks is also needed. This includes risks from new mixtures and chemicals (e.g. nanoparticles).
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