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. |
- Akdemir, KC, et al.
(författare)
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Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
- 2020
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 294-
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Tidskriftsartikel (refereegranskat)abstract
- Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
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3. |
- Cortes-Ciriano, I, et al.
(författare)
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Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
- 2020
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 331-
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Tidskriftsartikel (refereegranskat)abstract
- Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.
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4. |
- Li, YL, et al.
(författare)
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Patterns of somatic structural variation in human cancer genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1–7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.
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5. |
- 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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6. |
- Rodriguez-Martin, B, et al.
(författare)
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Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition
- 2020
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 306-
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Tidskriftsartikel (refereegranskat)abstract
- About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of 22 L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
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9. |
- Brors, Gunhild, et al.
(författare)
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Modes of e-Health delivery in secondary prevention programmes for patients with coronary artery disease : a systematic review
- 2019
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Ingår i: BMC Health Services Research. - : BioMed Central. - 1472-6963. ; 19, s. 1-24
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Forskningsöversikt (refereegranskat)abstract
- BackgroundElectronic health (e-Health) interventions are emerging as an effective alternative model for improving secondary prevention of coronary artery disease (CAD). The aim of this study was to describe the effectiveness of different modes of delivery and components in e-Health secondary prevention programmes on adherence to treatment, modifiable CAD risk factors and psychosocial outcomes for patients with CAD.MethodA systematic review was carried out based on articles found in MEDLINE, CINAHL, and Embase. Studies evaluating secondary prevention e-Health programmes provided through mobile-Health (m-Health), web-based technology or a combination of m-Health and web-based technology were eligible. The main outcomes measured were adherence to treatment, modifiable CAD risk factors and psychosocial outcomes. The quality appraisal of the studies included was conducted using the Joanna Briggs Institute critical appraisal tool for RCT. The results were synthesised narratively.ResultA total of 4834 titles were identified and 1350 were screened for eligibility. After reviewing 123 articles in full, 24 RCTs including 3654 participants with CAD were included. Eight studies delivered secondary prevention programmes through m-Health, nine through web-based technology, and seven studies used a combination of m-Health and web-based technology. The majority of studies employed two or three secondary prevention components, of which health education was employed in 21 studies. The m-Health programmes reported positive effects on adherence to medication. Most studies evaluating web-based technology programmes alone or in combination with m-Health also utilised traditional CR, and reported improved modifiable CAD risk factors. The quality appraisal showed a moderate methodological quality of the studies.ConclusionEvidence exists that supports the use of e-Health interventions for improving secondary prevention of CAD. However, a comparison across studies highlighted a wide variability of components and outcomes within the different modes of delivery. High quality trials are needed to define the most efficient mode of delivery and components capable of addressing a favourable outcome for patients.Trial registrationNot applicable.
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10. |
- Hansen, G, et al.
(författare)
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Retningslinjer for utredning og behandling av kronisk obstruktiv lungesykdom
- 1995
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Ingår i: Tidsskrift for Den Norske Lægeforening. - 0029-2001. ; 115:6, s. 710-713
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Tidskriftsartikel (refereegranskat)abstract
- A group of chest physicians, general practitioners, clinical pharmacologist and pharmacists appointed by the Institute of Pharmacotherapy, University of Oslo has evaluated the present knowledge about treatment of chronic obstructive lung disease. The group discusses today's medical treatment of this rather numerous group of patients. It is stated that, to a high degree, the treatment of these patients lacks proper documentation, and that treatment needs to be tested out on an individual basis. The group proposes a flow chart for this purpose.
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11. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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