| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
- Kang, E. Y., et al.
(författare)
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CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 129:5, s. 697-713
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
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| 3. |
- Kobel, M., et al.
(författare)
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p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Journal of Pathology Clinical Research. - : Wiley. - 2056-4538. ; 9:3, s. 208-222
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Tidskriftsartikel (refereegranskat)abstract
- Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
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| 4. |
- Scaife, A. A., et al.
(författare)
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Skillful long-range prediction of European and North American winters
- 2014
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 41:7, s. 2514-2519
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Tidskriftsartikel (refereegranskat)abstract
- Until recently, long-range forecast systems showed only modest levels of skill in predicting surface winter climate around the Atlantic Basin and associated fluctuations in the North Atlantic Oscillation at seasonal lead times. Here we use a new forecast system to assess seasonal predictability of winter North Atlantic climate. We demonstrate that key aspects of European and North American winter climate and the surface North Atlantic Oscillation are highly predictable months ahead. We demonstrate high levels of prediction skill in retrospective forecasts of the surface North Atlantic Oscillation, winter storminess, near-surface temperature, and wind speed, all of which have high value for planning and adaptation to extreme winter conditions. Analysis of forecast ensembles suggests that while useful levels of seasonal forecast skill have now been achieved, key sources of predictability are still only partially represented and there is further untapped predictability. The winter NAO can be skilfully predicted months ahead The signal-to-noise ratio of the predictable signal is anomalously low Predictions of the risk of regional winter extremes are possible
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| 5. |
- Folland, Chris K., et al.
(författare)
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The Summer North Atlantic Oscillation: past, present and future
- 2009
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Ingår i: Journal of Climate. - 0894-8755. ; 22:5, s. 1082-1103
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Tidskriftsartikel (refereegranskat)abstract
- Summer climate in the North Atlantic-European sector possesses a principal pattern of year-to-year variability that is the parallel of the well-known North Atlantic Oscillation in winter. This ‘Summer North Atlantic Oscillation’ (SNAO) is defined here as the first empirical orthogonal function (EOF) of observed summertime extratropical North Atlantic pressure at mean sea level. It is shown to be characterised by a more northerly location and smaller spatial scale than its winter counterpart. The SNAO is also detected by cluster analysis and has a near equivalent barotropic structure on daily and monthly time scales. Although of lesser amplitude than its wintertime counterpart, the SNAO exerts a strong influence on Northern European rainfall, temperature and cloudiness through changes in the position of the North Atlantic storm track. It is, therefore, of key importance in generating summer climate extremes, including flooding, drought and heat stress in North Western Europe. The El Niño/Southern Oscillation (ENSO) phenomenon is known to influence summertime European climate; however, interannual variations of the SNAO are only weakly influenced by ENSO. On interdecadal time scales, both modelling and observational results indicate that SNAO variations are partly related to the Atlantic Multidecadal Oscillation. It is shown that SNAO variations extend far back in time, as evidenced by reconstructions of SNAO variations back to 1706 using tree-ring records. Very long instrumental records, such as Central England Temperature, are used to validate the reconstruction. Finally, two climate models are shown to simulate the present-day SNAO and predict a trend towards a more positive index phase in the future under increasing greenhouse gas concentrations. This implies the long-term likelihood of increased summer drought for North Western Europe
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| 6. |
- Knight, J. R., et al.
(författare)
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Global meteorological influences on the record UK rainfall of winter 2013-14
- 2017
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 12:7
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Tidskriftsartikel (refereegranskat)abstract
- The UK experienced record average rainfall in winter 2013-14, leading to widespread and prolonged flooding. The immediate cause of this exceptional rainfall was a very strong and persistent cyclonic atmospheric circulation over the North East Atlantic Ocean. This was related to a very strong North Atlantic jet stream which resulted in numerous damaging wind storms. These exceptional meteorological conditions have led to renewed questions about whether anthropogenic climate change is noticeably influencing extreme weather. The regional weather pattern responsible for the extreme UK winter coincided with highly anomalous conditions across the globe. We assess the contributions from various possible remote forcing regions using sets of ocean-atmosphere model relaxation experiments, where winds and temperatures are constrained to be similar to those observed in winter 2013-14 within specified atmospheric domains. We find that influences from the tropics were likely to have played a significant role in the development of the unusual extra-tropical circulation, including a role for the tropical Atlantic sector. Additionally, a stronger and more stable stratospheric polar vortex, likely associated with a strong westerly phase of the stratospheric Quasi-Biennial Oscillation (QBO), appears to have contributed to the extreme conditions. While intrinsic climatic variability clearly has the largest effect on the generation of extremes, results from an analysis which segregates circulation-related and residual rainfall variability suggest that emerging climate change signals made a secondary contribution to extreme rainfall in winter 2013-14.
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| 7. |
- Philipp, Andreas, et al.
(författare)
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Long-Term Variability of Daily North Atlantic–European Pressure Patterns since 1850 Classified by Simulated Annealing Clustering
- 2007
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Ingår i: Journal of Climate. - 1520-0442. ; 20:16, s. 4065-4095
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Tidskriftsartikel (refereegranskat)abstract
- Reconstructed daily mean sea level pressure patterns of the North Atlantic–European region are classified for the period 1850 to 2003 to explore long-term changes of the atmospheric circulation and its impact on long-term temperature variability in the central European region. Commonly used k-means clustering algorithms resulted in classifications of low quality because of methodological deficiencies leading to local optima by chance for complex datasets. In contrast, a newly implemented clustering scheme combining the concepts of simulated annealing and diversified randomization (SANDRA) is able to reduce substantially the influence of chance in the cluster assignment, leading to partitions that are noticeably nearer to the global optimum and more stable. The differences between conventional cluster analysis and the SANDRA scheme are significant for subsequent analyses of single clusters—in particular, for trend analysis. Conventional indices used to determine the appropriate number of clusters failed to provide clear guidance, indicating that no distinct separation between clusters of circulation types exists in the dataset. Therefore, the number of clusters is determined by an external indicator, the so-called dominance criteria for t-mode principal component analysis. Nevertheless, the resulting partitions are stable for certain numbers of clusters and provide meaningful and reproducible clusters. The resulting types of pressure patterns reveal pronounced long-term variability and various significant trends of the time series of seasonal cluster frequency. Tentative estimations of central European temperature changes based solely on seasonal cluster frequencies can explain between 33.9% (summer) and 59.0% (winter) of temperature variance on the seasonal time scale. However, the signs of long-term changes in temperature are correctly reproduced even on multidecadal–centennial time scales. Moreover, linear warming trends are reproduced, implying from one-third up to one-half of the observed temperature increase between 1851/52 and 2003 (except for summer, but with significant trends for spring and autumn), indicating that changes in daily circulation patterns contribute to the observed overall long-term warming in the central European region.
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