| 1. |
- Johansson, Mattias, et al.
(författare)
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The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
- 2019
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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| 2. |
- Laskar, Ruhina S, et al.
(författare)
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Sex specific associations in genome wide association analysis of renal cell carcinoma.
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 27:10, s. 1589-1598
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Tidskriftsartikel (refereegranskat)abstract
- Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
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| 3. |
- Machiela, Mitchell J, et al.
(författare)
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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 72:5, s. 747-754
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
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| 4. |
- Scelo, Ghislaine, et al.
(författare)
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Genome-wide association study identifies multiple risk loci for renal cell carcinoma.
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
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| 5. |
- Sproson, Adam D., et al.
(författare)
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Osmium and lithium isotope evidence for weathering feedbacks linked to orbitally paced organic carbon burial and Silurian glaciations
- 2022
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Ingår i: Earth and Planetary Science Letters. - : Elsevier BV. - 0012-821X. ; 577
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Tidskriftsartikel (refereegranskat)abstract
- The Ordovician (∼487 to 443 Ma) ended with the formation of extensive Southern Hemisphere ice sheets, known as the Hirnantian glaciation, and the second largest mass extinction in Earth History. It was followed by the Silurian (∼443 to 419 Ma), one of the most climatically unstable periods of the Phanerozoic as evidenced by several large scale (>5‰) carbon isotope (δ13C) perturbations associated with further extinction events. Despite several decades of research, the cause of these environmental instabilities remains enigmatic. Here, we provide osmium (187Os/188Os) and lithium (δ7Li) isotope measurements of marine sedimentary rocks that cover four Silurian δ13C excursions. Osmium and Li isotope records resemble those previously recorded for the Hirnantian glaciation suggesting a similar causal mechanism. When combined with a new dynamic carbon-osmium-lithium biogeochemical model we suggest that astronomical forcing of the marine organic carbon cycle, as opposed to a decline in volcanic arc degassing or the rise of early land plants, resulted in drawdown of atmospheric CO2, triggering continental scale glaciation, intense global cooling and eustatic sea-level lows recognised in the geological record. Lower atmospheric pCO2 and temperatures during the Hirnantian and Silurian glaciations suppressed CO2 removal by silicate weathering, driving 187Os/188Os and δ7Li variability, supporting the existence of climate-regulating feedbacks.
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| 6. |
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| 7. |
- Chinnasamy, Sakthi Saravanan, et al.
(författare)
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Pressure, temperature, and timing of mineralization of the sedimentary rock-hosted orogenic gold deposit at Klipwal, southeastern Kaapvaal Craton, South Africa
- 2015
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Ingår i: Mineralium Deposita. - : Springer Science and Business Media LLC. - 0026-4598 .- 1432-1866. ; 50:6, s. 739-766
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Tidskriftsartikel (refereegranskat)abstract
- Gold mineralization in the Klipwal Shear Zone (KSZ) at the Klipwal Gold Mine is confined to laminated quartz-carbonate lodes, stringers, and associated alteration in sandstone and siltstone of the Delfkom Formation in the upper Mozaan Group of the Mesoarchaean Pongola Supergroup. The moderately dipping brittle-ductile KSZ strikes N-S with an oblique-reverse, sinistral sense of shear. The deformational events that are recognized include an early compressional phase that produced anastomosing shears defined by shear fabrics with numerous shear-parallel laminated quartz-carbonate fault-fill veins and, in places, extensional quartz vein stockworks, and a late brittle reactivation phase that produced fault breccias, displacing earlier extensional veins. Three closely spaced economic reefs (lodes) are developed: the main R-reef constitutes the KSZ, while the J- and H-reefs represent footwall splays. Alteration comprises chlorite, muscovite, epidote, feldspar, and carbonates along with pyrite, arsenopyrite, and chalcopyrite +/- pyrrhotite. An inner alteration zone is dominated by laminated quartz-carbonate veins with alternating quartz-carbonate-rich and muscovite-chlorite-rich laminae, whereas the proximal zone is characterized by alteration halos of K-feldspar, albite, epidote, chlorite, and muscovite along with carbonates and associated quartz veins. Chlorite thermometry from the inner and proximal zones yielded temperatures of 267 to 312 A degrees C. Arsenopyrite compositions provide temperatures in the same range, 255 to 318 A degrees C. Fluid inclusion microthermometry and Raman spectrometry of quartz veins in the mineralized reefs reveal the presence of metamorphogenic aqueous-gaseous fluid with an average salinity of 6.5 wt% NaCl equiv. Fluid compositions and estimated pressure-temperature (P-T) range (1.1 to 2.5 kbar at 255 to 318 A degrees C) are typical of orogenic gold deposits. Devolatilization during the regional facies metamorphism of the Pongola Supergroup is considered the likely fluid-forming event with fluid flow focused into a "compressional jog" of the KSZ. Shear-induced pressure fluctuations generated a phase separation of the initial aqueous-gaseous fluid, producing a gaseous and low-salinity aqueous fluid. This, together with fluid-rock interaction, and a decrease in fO(2) lead to sulfide and gold precipitation at Klipwal. Re-Os data from six sulfide samples constrain the age of sulfide precipitation and, by inference, gold mineralization, to 2563 A +/- 84 Ma, with an initial Os-187/Os-188 = 0.29 A +/- 0.08 (MSWD = 0.38). This age is distinctly younger than the post-Pongola granites (2863-2721 Ma), ruling out the association of granite emplacement with mineralization. This would suggest that mineralization is linked to the regional D-3 folding event which reactivated the KSZ after emplacement of the post-Pongola granites and that final brittle, post-mineralization reactivation is related to Karoo age faulting. Low initial Os values suggest that ore fluid interacted with mafic rocks, leaching non-radiogenic Os, the likely source being the deeper seated Nsuze Group volcanics and/or the greenstone belts that underlie the Pongola Supergroup.
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| 8. |
- Lawler, Mark, et al.
(författare)
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A Catalyst for Change: The European Cancer Patient's Bill of Rights.
- 2014
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Ingår i: The Oncologist. - : Oxford University Press (OUP). - 1549-490X .- 1083-7159.
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Tidskriftsartikel (refereegranskat)abstract
- The European Cancer Concord is a unique patient-centered partnership that will act as a catalyst to achieve improved access to an optimal standard of cancer care and research for European citizens. In order to provide tangible benefits for European cancer patients, the partnership proposes the creation of a “European Cancer Patient's Bill of Rights,” a patient charter that will underpin equitable access to an optimal standard of care for Europe's citizens.
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| 9. |
- Myint, Aung Zaw, et al.
(författare)
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Stable isotope and geochronological study of the Mawchi Sn-W deposit, Myanmar : Implications for timing of mineralization and ore genesis
- 2018
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Ingår i: Ore Geology Reviews. - : Elsevier BV. - 0169-1368. ; 95, s. 663-679
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Tidskriftsartikel (refereegranskat)abstract
- Myanmar is endowed with abundant Sn-W mineralization, pre-eminent amongst which is the world-class Mawchi deposit. In the Mawchi area, N-S trending vertical or steeply dipping quartz veins are hosted by both Eocene granite and Carboniferous to Early Permian metasediments. Three stages of ore formation are recognized; (i) tourmaline-cassiterite stage (ii) main ore stage and (iii) sulfide stage. Tourmaline, cassiterite and pyrite-I are early-formed minerals and are representative of the first stage. Their deposition continued together with wolframite, scheelite, molybdenite, arsenopyrite, pyrite-II, fluorite and danalite, which form the second stage. This was followed by the successive deposition of sulfides such as chalcopyrite, sphalerite, galena and Pb-Bi sulfides. A 40Ar/39Ar magmatic biotite plateau age of 41.50 ± 0.16 Ma (MSWD = 2.5) is determined for the Mawchi biotite granite which we interpret as the time the granite cooled through the biotite blocking temperature, and is consistent with a previously reported LA-ICP-MS U-Pb zircon concordia age of 42.72 ± 0.94 Ma (MSWD = 2). A molybdenite Re-Os model age of 42.4 ± 1.2 Ma indicates that Sn-W mineralization was synchronous with late Eocene granitic magmatism. Our 40Ar/39Ar hydrothermal muscovite plateau ages from the tourmaline granite (40.14 ± 0.14 Ma; MSWD = 1.48) and quartz vein selvages (40.80 ± 0.12 Ma; MSWD = 0.47) define the timing of hydrothermal alteration and simultaneous veining that accompanied the late stage of ore forming at Mawchi. Fluid inclusion microthermometry from cassiterite, scheelite, quartz, and fluorite reveals that ore fluids in the cassiterite-tourmaline stage and main ore stage are characterized by moderate homogenization temperatures (Th = 260–345 °C) and salinities (4.5–15.7 wt% NaCl equiv), while the sulfide stage is characterized by lower temperatures (Th = 175–260 °C) and moderate to low salinity (2.5–13 wt% NaCl equiv). The mean δ34S of all sulfides is 2.9 ± 2.9‰ which is suggestive that the overall system is dominated by magmatic sulfur. The similarity of δ34S values in galena and Pb-Bi sulfides (−1.3 to 2.7‰) suggest that sulfur, and inference the Pb and Bi were transported by a common fluid, probably of magmatic origin. The calculated δ18OH2O of the hydrothermal fluid associated with cassiterite and tourmaline is 7.3–8.4‰. Scheelite and quartz deposition is characterized by lighter δ18OH2O values (2.1–4.9‰) indicating that the ore fluid might be mixed with another source of water, perhaps, meteoric. Hydrogen isotopic compositions (δD = −51 to −121‰) again indicate that origin of the ore fluid is magmatic, but δD (∼−120‰) is low enough to support the δ18OH2O data that suggests, in part, a meteoric water component to the hydrothermal fluids at Mawchi.
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| 10. |
- Niklison-Chirou, Maria Victoria, et al.
(författare)
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TAp73 is a marker of glutamine addiction in medulloblastoma
- 2017
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Ingår i: Genes & Development. - : COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. - 0890-9369 .- 1549-5477. ; 31:17, s. 1738-1753
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.
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