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- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 5. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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- Adare, A, et al.
(författare)
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Azimuthal-Angle Dependence of Charged-Pion-Interferometry Measurements with Respect to Second- and Third-Order Event Planes in Au+Au Collisions at sqrt[s_{NN}]=200 GeV.
- 2014
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Ingår i: Physical Review Letters. - 1079-7114. ; 112:22
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Tidskriftsartikel (refereegranskat)abstract
- Charged-pion-interferometry measurements were made with respect to the second- and third-order event plane for Au+Au collisions at sqrt[s_{NN}]=200 GeV. A strong azimuthal-angle dependence of the extracted Gaussian-source radii was observed with respect to both the second- and third-order event planes. The results for the second-order dependence indicate that the initial eccentricity is reduced during the medium evolution, which is consistent with previous results. In contrast, the results for the third-order dependence indicate that the initial triangular shape is significantly reduced and potentially reversed by the end of the medium evolution, and that the third-order oscillations are largely dominated by the dynamical effects from triangular flow.
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| 7. |
- Adare, A., et al.
(författare)
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Azimuthal anisotropy of pi(0) and eta mesons in Au plus Au collisions at root s(NN)=200 GeV
- 2013
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 88:6
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Tidskriftsartikel (refereegranskat)abstract
- The azimuthal anisotropy coefficients v2 and v4 of p 0 and. mesons are measured in Au + Au collisions at root s(NN) = 200 GeV as a function of transverse momentum p(T) (1-14 GeV/c) and centrality. The extracted v(2) coefficients are found to be consistent between the two meson species over the measured p(T) range. The ratio of v(4)/v(2)(2) for pi(0) mesons is found to be independent of p(T) for 1- 9 GeV/c, implying a lack of sensitivity of the ratio to the change of underlying physics with p(T). Furthermore, the ratio of v(4)/v(2)(2) is systematically larger in central collisions, which may reflect the combined effects of fluctuations in the initial collision geometry and finite viscosity in the evolving medium.
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| 8. |
- Adare, A., et al.
(författare)
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Azimuthal Anisotropy of pi(0) Production in Au plus Au Collisions at root s(NN)=200 GeV: Path-Length Dependence of Jet Quenching and the Role of Initial Geometry
- 2010
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Ingår i: Physical Review Letters. - 1079-7114. ; 105:14
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Tidskriftsartikel (refereegranskat)abstract
- We have measured the azimuthal anisotropy of pi(0) production for 1 < p(T) < 18 GeV/c for Au + Au collisions at root s(NN) = 200 GeV. The observed anisotropy shows a gradual decrease for 3 less than or similar to p(T) less than or similar to 7-10 GeV/c, but remains positive beyond 10 GeV/c. The magnitude of this anisotropy is underpredicted, up to at least similar to 10 GeV/c, by current perturbative QCD (PQCD) energy-loss model calculations. An estimate of the increase in anisotropy expected from initial-geometry modification due to gluon saturation effects and fluctuations is insufficient to account for this discrepancy. Calculations that implement a path-length dependence steeper than what is implied by current PQCD energy-loss models show reasonable agreement with the data.
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| 9. |
- Adare, A., et al.
(författare)
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Azimuthal correlations of electrons from heavy-flavor decay with hadrons in p plus p and Au plus Au collisions at root s(NN)=200 GeV
- 2011
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 83:4
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of electrons from the decay of open-heavy-flavor mesons have shown that the yields are suppressed in Au+Au collisions compared to expectations from binary-scaled p+p collisions. These measurements indicate that charm and bottom quarks interact with the hot dense matter produced in heavy-ion collisions much more than expected. Here we extend these studies to two-particle correlations where one particle is an electron from the decay of a heavy-flavor meson and the other is a charged hadron from either the decay of the heavy meson or from jet fragmentation. These measurements provide more detailed information about the interactions between heavy quarks and the matter, such as whether the modification of the away-side-jet shape seen in hadron-hadron correlations is present when the trigger particle is from heavy-meson decay and whether the overall level of away-side-jet suppression is consistent. We statistically subtract correlations of electrons arising from background sources from the inclusive electron-hadron correlations and obtain two-particle azimuthal correlations at root s(NN) = 200 GeV between electrons from heavy-flavor decay with charged hadrons in p+p and also first results in Au+Au collisions. We find the away-side-jet shape and yield to be modified in Au+Au collisions compared to p+p collisions.
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| 10. |
- Adare, A., et al.
(författare)
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Centrality categorization Rp(d)+A in high-energy collisions
- 2014
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 90:3
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Tidskriftsartikel (refereegranskat)abstract
- High-energy proton- and deuteron-nucleus collisions provide an excellent tool for studying a wide array of physics effects, including modifications of parton distribution functions in nuclei, gluon saturation, and color neutralization and hadronization in a nuclear environment, among others. All of these effects are expected to have a significant dependence on the size of the nuclear target and the impact parameter of the collision, also known as the collision centrality. In this article, we detail a method for determining centrality classes in p(d) + A collisions via cuts on the multiplicity at backward rapidity (i.e., the nucleus-going direction) and for determining systematic uncertainties in this procedure. For d + Au collisions at root s(NN) = 200 GeV we find that the connection to geometry is confirmed by measuring the fraction of events in which a neutron from the deuteron does not interact with the nucleus. As an application, we consider the nuclear modification factors Rp(d)+A, for which there is a bias in the measured centrality-dependent yields owing to auto correlations between the process of interest and the backward-rapidity multiplicity. We determine the bias-correction factors within this framework. This method is further tested using the HIJING Monte Carlo generator. We find that for d + Au collisions at root s(NN) = 200 GeV, these bias corrections are small and vary by less than 5% (10%) up to p(T) = 10 (20) GeV/c. In contrast, for p + Pb collisions at v root s(NN) = 5.02 TeV we find that these bias factors are an order of magnitude larger and strongly pT dependent, likely attributable to the larger effect of multiparton interactions.
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