| 1. |
- Machiela, Mitchell J., et al.
(author)
-
Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
-
In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
-
Journal article (peer-reviewed)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
|
|
| 2. |
- Machiela, Mitchell J, et al.
(author)
-
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
-
In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- McKay, James D., et al.
(author)
-
Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
-
In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
-
Journal article (peer-reviewed)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
|
|
| 6. |
- Pearce, Neil E, et al.
(author)
-
IARC Monographs : 40 Years of Evaluating Carcinogenic Hazards to Humans
- 2015
-
In: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 123:6, s. 507-514
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Recently the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also the approach used to perform these evaluations. Some critics have claimed that IARC Working Groups' failures to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.OBJECTIVES: The authors of this paper are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We have examined here criticisms of the IARC classification process to determine the validity of these concerns. We review the history of IARC evaluations and describe how the IARC evaluations are performed.DISCUSSION: We conclude that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various discipline and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.
|
|
| 7. |
- Acciarri, R., et al.
(author)
-
Demonstration of MeV-scale physics in liquid argon time projection chambers using ArgoNeuT
- 2019
-
In: Physical Review D. - : AMER PHYSICAL SOC. - 2470-0010 .- 2470-0029. ; 99:1
-
Journal article (peer-reviewed)abstract
- MeV-scale energy depositions by low-energy photons produced in neutrino-argon interactions have been identified and reconstructed in ArgoNeuT liquid argon time projection chamber (LArTPC) data. ArgoNeuT data collected on the NuMI beam at Fermilab were analyzed to select isolated low-energy depositions in the TPC volume. The total number, reconstructed energies, and positions of these depositions have been compared to those from simulations of neutrino-argon interactions using the FLUKA Monte Carlo generator. Measured features are consistent with energy depositions from photons produced by deexcitation of the neutrino's target nucleus and by inelastic scattering of primary neutrons produced by neutrino-argon interactions. This study represents a successful reconstruction of physics at the MeV scale in a LArTPC, a capability of crucial importance for detection and reconstruction of supernova and solar neutrino interactions in future large LArTPCs.
|
|
| 8. |
- Hung, Rayjean J., et al.
(author)
-
Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region
- 2019
-
In: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 14:8, s. 1360-1369
-
Journal article (peer-reviewed)abstract
- Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
|
|
| 9. |
- Landälv, Ludvig, 1982-, et al.
(author)
-
Structural evolution in reactive RF magnetron sputtered (Cr,Zr)2O3 coatings during annealing
- 2017
-
In: Acta Materialia. - : PERGAMON-ELSEVIER SCIENCE LTD. - 1359-6454 .- 1873-2453. ; 131, s. 543-552
-
Journal article (peer-reviewed)abstract
- Reactive RF-magnetron sputtering is used to grow Cr0.28Zr0.10O0.61 coatings at 500 degrees C. Coatings are annealed at 750 degrees C, 810 degrees C, and 870 degrees C. The microstructure evolution of the pseudobinary oxide compound is characterized through high resolution state of the art HRSTEM and HREDX-maps, revealing the segregation of Cr and Zr on the nm scale. The as-deposited coating comprises cc-(Cr,Zr)(2)O-3 solid solution with a Zr-rich (Zr,Cr)O-x. amorphous phase. After annealing to 750 degrees C tetragonal ZrO2 nucleates and grows from the amorphous phase. The ZrO2 phase is stabilized in its tetragonal structure at these fairly low annealing temperatures, possibly due to the small grain size (below 30 nm). Correlated with the nucleation and growth of the tetragonal-ZrO2 phase is an increase in hardness, with a maximum hardness after annealing to 750 degrees C, followed by a decrease in hardness upon coarsening, bcc metallic Cr phase formation and loss of oxygen, during annealing to 870 degrees C. The observed phase segregation opens up future design routes for pseudobinary oxides with tunable microstructural and mechanical properties. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
|
|
