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- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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- Osorio, A., et al.
(författare)
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Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2 (CIMBA)
- 2009
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Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 101:12, s. 2048-2054
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Tidskriftsartikel (refereegranskat)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, P0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
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- Osorio, A., et al.
(författare)
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Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2
- 2011
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 104:8, s. 1356-1361
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers. British Journal of Cancer (2011) 104, 1356-1361. doi:10.1038/bjc.2011.91 www.bjcancer.com Published online 22 March 2011 (C) 2011 Cancer Research UK
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- Martrat, Griselda, et al.
(författare)
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Exploring the link between MORF4L1 and risk of breast cancer
- 2011
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
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- De Frenne, Pieter, et al.
(författare)
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Biological Flora of the British Isles : Milium effusum
- 2017
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Ingår i: Journal of Ecology. - : Wiley. - 0022-0477 .- 1365-2745. ; 105:3, s. 839-858
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Tidskriftsartikel (refereegranskat)abstract
- 1. This account presents information on all aspects of the biology of Milium effusum L. (Wood Millet) that are relevant to understanding its ecological characteristics and behaviour. The main topics are presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history, and conservation.2. The grass Milium effusum is a common species of mature woodland in central and southern England, but is less common in the wetter parts of northern England, Wales, Scotland and Ireland. Worldwide, the species is native to many temperate, boreal, subarctic and subalpine parts of the northern hemisphere: from eastern North America across most of Europe (excluding Mediterranean climates) to the Ural Mountains and Black Sea, extending eastwards to the Himalaya, Korea and Japan.3. Wood Millet is a shade-tolerant, relatively tall grass (up to 1.8 m) producing up to 700 caryopses per individual. It is characteristic of temperate deciduous woodland, but can also occur in other woodland and forest types and even in scrub, alpine meadows, along railways and roads, and on rocks. In woods, it is one of the most conspicuous plants of the herb layer in the early summer after the disappearance of spring flowering species. While the species is generally considered an ancient woodland indicator in England and western Europe, it is also known to colonize secondary, post-agricultural forests relatively rapidly in other areas such as Denmark, southern Sweden and Poland.4. The species has a wide amplitude in terms of soil acidity and nutrient availability, but predominantly grows on soils of intermediate soil fertility and soil pH and with high organic matter concentration. However, M. effusum can tolerate large quantities of tree-leaf litter on the forest floor and is able to grow on very acidic soils.5. Changes in land use, climate, densities of large herbivores and atmospheric deposition of nitrogen are having effects on populations of Wood Millet. Significant responses of the life-history traits and population characteristics have been detected in response to environmental variation and to experimental treatments of temperature, nutrients, light and acidity. In many of its habitats across its range, M. effusum is currently becoming more frequent. During the last century, its mean elevation of occurrence in upland areas of Europe has also increased by several hundreds of metres. Typically, management actions are directed towards the conservation of its main habitat type (e.g. ancient woodlands of the Milio-Fagetum association) rather than to the species specifically.
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- Helsen, Kenny, et al.
(författare)
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No genetic erosion after five generations for Impatiens glandulifera populationsacross the invaded range in Europe
- 2019
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Ingår i: BMC Genetics. - : BioMed Central. - 1471-2156. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Background: The observation that many alien species become invasive despite low genetic diversity has long been considered the ‘genetic paradox’ in invasion biology. This paradox is often resolved through the temporal buildup genetic diversity through multiple introduction events. These temporal dynamics in genetic diversity are especially important for annual invasive plants that lack a persistent seed bank, for which population persistence is strongly dependent on consecutive seed ‘re-establishment’ in each growing season. Theory predicts that the number of seeds during re-establishment, and the levels of among-population gene flow can strongly affect recolonization dynamics, resulting in either an erosion or build-up of population genetic diversity through time. This study focuses on temporal changes in the population genetic structure of the annual invasive plant Impatiens glandulifera across Europe. We resampled 13 populations in 6 regions along a 1600 km long latitudinal gradient from northern France to central Norway after 5 years, and assessed population genetic diversity with 9 microsatellite markers.Results: Our study suggests sufficiently high numbers of genetically diverse founders during population re- establishment, which prevent the erosion of local genetic diversity. We furthermore observe that I. glanduliferaexperiences significant among-population gene flow, gradually resulting in higher genetic diversity and lower overall genetic differentiation through time. Nonetheless, moderate founder effects concerning population genetic composition (allele frequencies) were evident, especially for smaller populations.Despite the initially low genetic diversity, this species seems to be successful at persisting across its invaded range, and will likely continue to build up higher genetic diversity at the local scale.
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