| 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. |
- Rheinbay, E, et al.
(författare)
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Analyses of non-coding somatic drivers in 2,658 cancer whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 102-
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.
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| 3. |
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| 4. |
- Carlevaro-Fita, J, et al.
(författare)
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Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis
- 2020
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1, s. 56-
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Tidskriftsartikel (refereegranskat)abstract
- Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.
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| 5. |
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| 6. |
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| 7. |
- Bernardi, G., et al.
(författare)
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The Future Circular Collider : a Summary for the US 2021 Snowmass Process
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In this white paper for the 2021 Snowmass process, we give a description of the proposed Future Circular Collider (FCC) project and its physics program. The paper summarizes and updates the discussion submitted to the European Strategy on Particle Physics. After construction of an approximately 90 km tunnel, an electron-positron collider based on established technologies allows world-record instantaneous luminosities at center-of-mass energies from the Z resonance up to tt thresholds, enabling a rich set of fundamental measurements including Higgs couplings determinations at the sub percent level, precision tests of the weak and strong forces, and searches for new particles, including dark matter, both directly and via virtual corrections or mixing. Among other possibilities, the FCC-ee will be able to (i) indirectly discover new particles coupling to the Higgs and/or electroweak bosons up to scales around 7 and 50 TeV, respectively; (ii) perform competitive SUSY tests at the loop level in regions not accessible at the LHC; (iii) study heavy-flavor and tau physics in ultra-rare decays beyond the LHC reach, and (iv) achieve the best potential in direct collider searches for dark matter, sterile neutrinos, and axion-like particles with masses up to around 90 GeV. The tunnel can then be reused for a proton-proton collider, establishing record center-of-mass collision energy, allowing unprecedented reach for direct searches for new particles up to the around 50 TeV scale, and a diverse program of measurements of the Standard Model and Higgs boson, including a precision measurement of the Higgs self-coupling, and conclusively testing weakly-interacting massive particle scenarios of thermal relic dark matter.
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| 8. |
- Cirigliano, V., et al.
(författare)
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A complete update of ε0/ε in the standard model
- 2019
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Ingår i: European Physical Society Conference on High Energy Physics (EPS-HEP2019). - Trieste, Italy : Sissa Medialab. - 1824-8039. ; 364
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Konferensbidrag (refereegranskat)abstract
- The recent release of improved lattice data has revived again the interest on precise theoretical calculations of the direct CP-violation ratio ε0/ε. We present a complete update of the Standard Model prediction [1,2], including a new re-analysis of isospin-breaking corrections which are of vital importance in the theoretical determination of this observable. The Standard Model prediction, Re(ε0/ε) = (14±5)·10−4, turns out to be in good agreement with the experimental measurement.
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| 9. |
- Cirigliano, V., et al.
(författare)
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Isospin-breaking contributions to ϵ ′/ϵ
- 2020
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Ingår i: International Conference on Kaon Physics 2019 10-13 September 2019, University of Perugia, Italy. - : IOP Publishing. - 1742-6588. ; 1526
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Konferensbidrag (refereegranskat)abstract
- We present an updated analysis of isospin-violating corrections to ϵ0=ϵ in the framework of chiral perturbation theory, taking advantage of the currently improved knowledge on quark masses and nonperturbative parameters. The role of the different ingredients entering into the analysis is carefully assessed. Our final result is ωeff = 0:110 +0:090 -0:088 [1].
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| 10. |
- Cirigliano, V., et al.
(författare)
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Isospin-violating contributions to ∈′/∈
- 2020
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Ingår i: Journal of High Energy Physics. - 1029-8479. ; 2020:2
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Tidskriftsartikel (refereegranskat)abstract
- The known isospin-breaking contributions to the K → ππ amplitudes are reanalyzed, taking into account our current understanding of the quark masses and the relevant non-perturbative inputs. We present a complete numerical reappraisal of the direct CP-violating ratio ∈′/∈, where these corrections play a quite significant role. We obtain the Standard Model prediction Re (∈′/∈) = (14 ± 5) · 10−4, which is in very good agreement with the measured ratio. The uncertainty, which has been estimated conservatively, is dominated by our current ignorance about 1/NC-suppressed contributions to some relevant chiral-perturbation-theory low-energy constants.
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