| 1. |
- Rothman, Nathaniel, et al.
(författare)
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A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 978-984
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
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| 2. |
- Ade, Peter, et al.
(författare)
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The Simons Observatory : science goals and forecasts
- 2019
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2
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Tidskriftsartikel (refereegranskat)abstract
- The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial con figuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping approximate to 10% of the sky to a white noise level of 2 mu K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of sigma(r) = 0.003. The large aperture telescope will map approximate to 40% of the sky at arcminute angular resolution to an expected white noise level of 6 mu K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
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| 3. |
- Berrout, Jonathan, et al.
(författare)
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TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Recent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD), where its role and mechanism of action remain unknown. We have previously established that the membrane receptor FGFR2 drives LUAD progression through aberrant protein-protein interactions mediated via its C-terminal proline-rich motif. Here we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline-rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2, hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.
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| 4. |
- Clausen, Thomas Mandel, et al.
(författare)
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A simple method for detecting oncofetal chondroitin sulfate glycosaminoglycans in bladder cancer urine
- 2020
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Ingår i: Cell Death Discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Proteoglycans in bladder tumors are modified with a distinct oncofetal chondroitin sulfate (ofCS) glycosaminoglycan that is normally restricted to placental trophoblast cells. This ofCS-modification can be detected in bladder tumors by the malarial VAR2CSA protein, which in malaria pathogenesis mediates adherence of parasite-infected erythrocytes within the placenta. In bladder cancer, proteoglycans are constantly shed into the urine, and therefore have the potential to be used for detection of disease. In this study we investigated whether recombinant VAR2CSA (rVAR2) protein could be used to detect ofCS-modified proteoglycans (ofCSPGs) in the urine of bladder cancer patients as an indication of disease presence. We show that ofCSPGs in bladder cancer urine can be immobilized on cationic nitrocellulose membranes and subsequently probed for ofCS content by rVAR2 protein in a custom-made dot-blot assay. Patients with high-grade bladder tumors displayed a marked increase in urinary ofCSPGs as compared to healthy individuals. Urine ofCSPGs decreased significantly after complete tumor resection compared to matched urine collected preoperatively from patients with bladder cancer. Moreover, ofCSPGs in urine correlated with tumor size of bladder cancer patients. These findings demonstrate that rVAR2 can be utilized in a simple biochemical assay to detect cancer-specific ofCS-modifications in the urine of bladder cancer patients, which may be further developed as a noninvasive approach to detect and monitor the disease.
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| 5. |
- Dyrskjøt, Lars, et al.
(författare)
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Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma : a multicenter validation study
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:12, s. 3545-3551
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Clinically useful molecular markers predicting the clinical course of patients diagnosed with non–muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression. Experimental Design: We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome. Results: Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of Ta or T1 tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis. Conclusion: This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non–muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.
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| 6. |
- Foth, Mona, et al.
(författare)
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FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation
- 2018
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417. ; 246:3, s. 331-343
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies of muscle-invasive bladder cancer show that FGFR3 mutations are generally found in a luminal papillary tumour subtype that is characterised by better survival than other molecular subtypes. To better understand the role of FGFR3 in invasive bladder cancer, we examined the process of tumour development induced by the tobacco carcinogen OH-BBN in genetically engineered models that express mutationally activated FGFR3 S249C or FGFR3 K644E in the urothelium. Both occurrence and progression of OH-BBN-driven tumours were increased in the presence of an S249C mutation compared to wild-type control mice. Interestingly, at an early tumour initiation stage, the acute inflammatory response in OH-BBN-treated bladders was suppressed in the presence of an S249C mutation. However, at later stages of tumour progression, increased inflammation was observed in S249C tumours, long after the carcinogen administration had ceased. Early-phase neutrophil depletion using an anti-Ly6G monoclonal antibody resulted in an increased neutrophil-to-lymphocyte ratio at later stages of pathogenesis, indicative of enhanced tumour pathogenesis, which supports the hypothesis that suppression of acute inflammation could play a causative role. Statistical analyses of correlation showed that while initial bladder phenotypes in morphology and inflammation were FGFR3-dependent, increased levels of inflammation were associated with tumour progression at the later stage. This study provides a novel insight into the tumour-promoting effect of FGFR3 mutations via regulation of inflammation at the pre-tumour stage in the bladder.
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| 7. |
- Hurst, Carolyn D., et al.
(författare)
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Stage-stratified molecular profiling of non-muscle-invasive bladder cancer enhances biological, clinical, and therapeutic insight
- 2021
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Ingår i: Cell Reports Medicine. - : Elsevier BV. - 2666-3791. ; 2:12
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the molecular determinants that underpin the clinical heterogeneity of non-muscle-invasive bladder cancer (NMIBC) is essential for prognostication and therapy development. Stage T1 disease in particular presents a high risk of progression and requires improved understanding. We present a detailed multi-omics study containing gene expression, copy number, and mutational profiles that show relationships to immune infiltration, disease recurrence, and progression to muscle invasion. We compare expression and genomic subtypes derived from all NMIBCs with those derived from the individual disease stages Ta and T1. We show that sufficient molecular heterogeneity exists within the separate stages to allow subclassification and that this is more clinically meaningful for stage T1 disease than that derived from all NMIBCs. This provides improved biological understanding and identifies subtypes of T1 tumors that may benefit from chemo- or immunotherapy.
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| 8. |
- Kiemeney, Lambertus A, et al.
(författare)
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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| 9. |
- Marzouka, Nour-Al-Dain, et al.
(författare)
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The Lund Molecular Taxonomy Applied to Non-Muscle-Invasive Urothelial Carcinoma
- 2022
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Ingår i: Journal of Molecular Diagnostics. - : Elsevier BV. - 1525-1578. ; 24:9, s. 992-1008
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Tidskriftsartikel (refereegranskat)abstract
- The precise classification of tumors into relevant molecular subtypes will facilitate both future research and optimal treatment. Here, the Lund Taxonomy system for molecular classification of urothelial carcinoma was applied to two large and independent cohorts of non-muscle-invasive tumors. Of 752 tumors classified, close to 100% were of the luminal subtypes, 95% urothelial-like (Uro; UroA, UroB, or UroC) and 5% genomically unstable. The obtained subtype structure organized the tumors into groups with specific and coherent gene mutation, genomic, and clinical profiles. The intrasubtype variability in the largest group of tumors, UroA, was caused by infiltration and proliferation, not considered as cancer cell type-defining properties. Within the UroA subtype, a HOXB/late cell-cycle gene expression polarity was found, strongly associated with FGFR3, STAG2, and TP53 mutations, as well as with chromosome 9 losses. Kaplan-Meier analyses identified the genomically unstable subtype as a progression high-risk group, also valid in the subgroup of T1 tumors. Almost all progression events occurred within 12 months in this subtype. Also, a general progression gene signature was derived that identifies high- and low-risk tumors. All findings were demonstrated in two independent cohorts. The Lund Taxonomy system is applicable to both non-muscle- and muscle-invasive tumors and may be a useful biological framework for translational studies.
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| 10. |
- Purcell, Shaun M., et al.
(författare)
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Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 460:7256, s. 748-752
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
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