| 1. |
- Ferreira, MA, et al.
(författare)
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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1741-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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| 2. |
- Barnes, DR, et al.
(författare)
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Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores
- 2022
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 114:1, s. 109-122
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRecent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.Methods483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.ResultsPRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.ConclusionsPopulation-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
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| 3. |
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| 4. |
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| 5. |
- Hakkaart, C, et al.
(författare)
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Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 1061-
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
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| 6. |
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| 7. |
- Knoepp, F., et al.
(författare)
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Development of a Gas-Tight Microfluidic System for Raman Sensing of Single Pulmonary Arterial Smooth Muscle Cells Under Normoxic/Hypoxic Conditions
- 2018
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Ingår i: Sensors. - Basel, Switzerland : MDPI. - 1424-8220. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Acute hypoxia changes the redox-state of pulmonary arterial smooth muscle cells (PASMCs). This might influence the activity of redox-sensitive voltage-gated K⁺-channels (Kv-channels) whose inhibition initiates hypoxic pulmonary vasoconstriction (HPV). However, the molecular mechanism of how hypoxia-or the subsequent change in the cellular redox-state-inhibits Kv-channels remains elusive. For this purpose, a new multifunctional gas-tight microfluidic system was developed enabling simultaneous single-cell Raman spectroscopic studies (to sense the redox-state under normoxic/hypoxic conditions) and patch-clamp experiments (to study the Kv-channel activity). The performance of the system was tested by optically recording the O₂-content and taking Raman spectra on murine PASMCs under normoxic/hypoxic conditions or in the presence of H₂O₂. Oxygen sensing showed that hypoxic levels in the gas-tight microfluidic system were achieved faster, more stable and significantly lower compared to a conventional open system (1.6 ± 0.2%, respectively 6.7 ± 0.7%, n = 6, p < 0.001). Raman spectra revealed that the redistribution of biomarkers (cytochromes, FeS, myoglobin and NADH) under hypoxic/normoxic conditions were improved in the gas-tight microfluidic system (p-values from 0.00% to 16.30%) compared to the open system (p-value from 0.01% to 98.42%). In conclusion, the new redox sensor holds promise for future experiments that may elucidate the role of Kv-channels during HPV.
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| 8. |
- Ramser, Kerstin, et al.
(författare)
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Importance of substrate and photo-induced effects in Raman spectroscopy of single functional erythrocytes
- 2003
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Ingår i: Journal of Biomedical Optics. - : SPIE-Intl Soc Optical Eng. - 1083-3668 .- 1560-2281. ; 8:2, s. 173-178
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Tidskriftsartikel (refereegranskat)abstract
- Hemoglobin (Hb) in single erythrocytes (red blood cells), adsorbed on polylysine-coated glass surfaces, was studied using resonance Raman spectroscopy and global Raman imaging. The erythrocytes were found to be sensitive to both surface adsorption and laser illumination. Substrate-dependent changes of the cell membrane shape were observed immediately after cell adsorption, while a photo-induced increase of fluorescence was observed for visible excitation (λ=514.5 nm). Concurrent changes in Raman spectra revealed a conversion of oxy-Hb (2+) to the inactive met-Hb state (3+). These effects severely complicate the interpretation of Raman images. However, at a low accumulated photon dose, the preparation method enabled the recording of Raman spectra during the oxygenation cycle of a single erythrocyte in buffer, which illustrates the feasibility of Raman investigations of functional cells in in-vivo environments.
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| 9. |
- Ramser, Kerstin, et al.
(författare)
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Raman imaging and spectroscopy of single functional erythrocytes : a feasibility study
- 2002
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Ingår i: Biomedical vibrational spectroscopy II. - : SPIE - International Society for Optical Engineering. - 0819443530 ; , s. 20-27
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Konferensbidrag (refereegranskat)abstract
- Hemoglobin (Hb) within single erythrocytes (red blood cells), adsorbed on poly-lysine coated glass surfaces, was studied using resonance Raman spectroscopy and global Raman imaging. The erythrocytes were found to be sensitive to both surface adsorption and to the laser light. Topological changes of the cell membrane were observed immediately after cell adsorption in Raman images. We observed a photo-induced increase of the fluorescence background occurring simultaneously with a decrease in the Hb Raman signal. Concurrent changes in Raman spectra revealed a conversion of oxy-Hb to the met-Hb state. However, at a low accumulated photon dose, the preparation method enabled the recording of Raman spectra during the oxygenation cycle of a single red blood cell in buffer, which shows that Hb was in an in-vivo environment. Thus, Raman spectroscopy of functional Hb in isolated red blood cells is feasible.
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| 10. |
- Trandafir, F., et al.
(författare)
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Neuroglobin and cytoglobin as potential enzyme or substrate
- 2007
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Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 398:1-2, s. 103-113
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Tidskriftsartikel (refereegranskat)abstract
- The possible enzymatic activities of neuro- and cytoglobin as well as their potential function as substrates in enzymatic reactions were studied. Neuro- and cytoglobin are found to show no appreciable superoxide dismutase, catalase, and peroxidase activities. However, the internal disulfide bond (CD7-D5) of human neuroglobin can be reduced by thioredoxin reductase. Furthermore, our in vivo and in vitro studies show that Escherichia coli cells contain an enzymatic reducing system that keeps the heme iron atom of neuroglobin in the Fe2+ form in the presence of dioxygen despite the high autoxidation rate of the molecule. This reducing system needs a low-molecular-weight compound as co-factor. In vitro tests show that both NADH and NADPH can play this role. Furthermore, the reducing system is not specific for neuroglobin but allows the reduction of the ferric forms of other globins such as cytoglobin and myoglobin. A similar reducing system is present in eukaryotic tissue protein extracts.
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