| 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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| 4. |
- Belczynski, K., et al.
(författare)
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Evolutionary roads leading to low effective spins, high black hole masses, and O1/O2 rates for LIGO/Virgo binary black holes
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 636:A&A
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Tidskriftsartikel (refereegranskat)abstract
- All ten LIGO/Virgo binary black hole (BH-BH) coalescences reported following the O1/O2 runs have near-zero effective spins. There are only three potential explanations for this. If the BH spin magnitudes are large, then: (i) either both BH spin vectors must be nearly in the orbital plane or (ii) the spin angular momenta of the BHs must be oppositely directed and similar in magnitude. Then there is also the possibility that (iii) the BH spin magnitudes are small. We consider the third hypothesis within the framework of the classical isolated binary evolution scenario of the BH-BH merger formation. We test three models of angular momentum transport in massive stars: A mildly efficient transport by meridional currents (as employed in the Geneva code), an efficient transport by the Tayler-Spruit magnetic dynamo (as implemented in the MESA code), and a very-efficient transport (as proposed by Fuller et al.) to calculate natal BH spins. We allow for binary evolution to increase the BH spins through accretion and account for the potential spin-up of stars through tidal interactions. Additionally, we update the calculations of the stellar-origin BH masses, including revisions to the history of star formation and to the chemical evolution across cosmic time. We find that we can simultaneously match the observed BH-BH merger rate density and BH masses and BH-BH effective spins. Models with efficient angular momentum transport are favored. The updated stellar-mass weighted gas-phase metallicity evolution now used in our models appears to be key for obtaining an improved reproduction of the LIGO/Virgo merger rate estimate. Mass losses during the pair-instability pulsation supernova phase are likely to be overestimated if the merger GW170729 hosts a BH more massive than 50âMâŠ. We also estimate rates of black hole-neutron star (BH-NS) mergers from recent LIGO/Virgo observations. If, in fact. angular momentum transport in massive stars is efficient, then any (electromagnetic or gravitational wave) observation of a rapidly spinning BH would indicate either a very effective tidal spin up of the progenitor star (homogeneous evolution, high-mass X-ray binary formation through case A mass transfer, or a spin-up of a Wolf-Rayet star in a close binary by a close companion), significant mass accretion by the hole, or a BH formation through the merger of two or more BHs (in a dense stellar cluster).
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| 5. |
- Reulen, RC, et al.
(författare)
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Risk of digestive cancers in a cohort of 69 460 five-year survivors of childhood cancer in Europe: the PanCareSurFup study
- 2021
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 70:8, s. 1520-1528
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Tidskriftsartikel (refereegranskat)abstract
- Survivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide.MethodsThe PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence.Results427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN—comparable to the risk among members of the general population with at least two first-degree relatives affected.ConclusionsColonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken.
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| 6. |
- Li, Constance H., et al.
(författare)
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Sex differences in oncogenic mutational processes
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
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| 7. |
- Kaiser, T., et al.
(författare)
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Electrical and mechanical behaviour of metal thin films with deformation-induced cracks predicted by computational homogenisation
- 2021
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Ingår i: International Journal of Fracture. - : Springer Science and Business Media LLC. - 0376-9429 .- 1573-2673. ; 231:2, s. 223-242
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Tidskriftsartikel (refereegranskat)abstract
- Motivated by advances in flexible electronic technologies and by the endeavour to develop non-destructive testing methods, this article analyses the capability of computational multiscale formulations to predict the influence of microscale cracks on effective macroscopic electrical and mechanical material properties. To this end, thin metal films under mechanical load are experimentally analysed by using in-situ confocal laser scanning microscopy (CLSM) and in-situ four point probe resistance measurements. Image processing techniques are then used to generate representative volume elements from the laser intensity images. These discrete representations of the crack pattern at the microscale serve as the basis for the calculation of effective macroscopic electrical conductivity and mechanical stiffness tensors by means of computational homogenisation approaches. A comparison of simulation results with experimental electrical resistance measurements and a detailed study of fundamental numerical properties demonstrates the applicability of the proposed approach. In particular, the (numerical) errors that are induced by the representative volume element size and by the finite element discretisation are studied, and the influence of the filter that is used in the generation process of the representative volume element is analysed.
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| 8. |
- Åkesson, Susanne, et al.
(författare)
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Evolution of chain migration in an aerial insectivorous bird, the common swift Apus apus
- 2020
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Ingår i: Evolution. - : Wiley. - 0014-3820 .- 1558-5646. ; 74:10, s. 2377-2391
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Tidskriftsartikel (refereegranskat)abstract
- Spectacular long-distance migration has evolved repeatedly in animals enabling exploration of resources separated in time and space. In birds, these patterns are largely driven by seasonality, cost of migration, and asymmetries in competition leading most often to leapfrog migration, where northern breeding populations winter furthest to the south. Here, we show that the highly aerial common swift Apus apus, spending the nonbreeding period on the wing, instead exhibits a rarely found chain migration pattern, where the most southern breeding populations in Europe migrate to wintering areas furthest to the south in Africa, whereas the northern populations winter to the north. The swifts concentrated in three major areas in sub-Saharan Africa during the nonbreeding period, with substantial overlap of nearby breeding populations. We found that the southern breeding swifts were larger, raised more young, and arrived to the wintering areas with higher seasonal variation in greenness (Normalized Difference Vegetation Index) earlier than the northern breeding swifts. This unusual chain migration pattern in common swifts is largely driven by differential annual timing and we suggest it evolves by prior occupancy and dominance by size in the breeding quarters and by prior occupancy combined with diffuse competition in the winter.
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