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| 2. |
- Thomas, HS, et al.
(author)
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- 2019
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swepub:Mat__t
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- Glasbey, JC, et al.
(author)
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- 2021
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- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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| 11. |
- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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| 13. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)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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- Mishra, A, et al.
(author)
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Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
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Journal article (peer-reviewed)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
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- Carninci, P, et al.
(author)
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The transcriptional landscape of the mammalian genome
- 2005
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In: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
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Journal article (peer-reviewed)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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| 35. |
- Dareng, EO, et al.
(author)
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- 2022
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In: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 30:3, s. 349-362
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Journal article (peer-reviewed)abstract
- Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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| 36. |
- Du, QQ, et al.
(author)
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FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis
- 2022
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In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 13:5, s. 488-
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Journal article (peer-reviewed)abstract
- Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC.
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| 40. |
- Hillmer, AM, et al.
(author)
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Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes
- 2011
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In: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 21:5, s. 665-675
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Journal article (peer-reviewed)abstract
- Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA–PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers.
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| 43. |
- Lee, KS, et al.
(author)
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Bridging thrombolysis improves survival rates at 90 days compared with direct mechanical thrombectomy alone in acute ischemic stroke due to basilar artery occlusion: a systematic review and meta-analysis of 1096 patients
- 2023
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In: Journal of neurointerventional surgery. - : BMJ. - 1759-8486 .- 1759-8478. ; 15:10, s. 1039-1045
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Journal article (peer-reviewed)abstract
- Mechanical thrombectomy (MT) is an effective treatment for patients with acute ischemic stroke (AIS) from basilar artery occlusion (BAO).ObjectiveTo compare the clinical outcomes of MT, with and without bridging intravenous thrombolysis (IVT), in acute BAO through a systematic review and meta-analysis of the current literature.MethodsSystematic searches of Medline, EMBASE, and Cochrane Central were undertaken on August 1, 2022. Good functional outcome defined as 90-day modified Rankin Scale score 0–2 was the primary outcome measure. Secondary outcome measures were 90-day mortality, successful post-thrombectomy recanalization (modified Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracranial hemorrhage (sICH), and subarachnoid hemorrhage (SAH).ResultsThree studies reporting 1096 patients with BAO AIS were included in the meta-analysis. No significant differences in good functional outcome were detected between the two groups (RR=1.28 (95% CI 0.86 to 1.92); p=0.117). However, specifically patients with large artery atherosclerosis (LAA) benefited from bridging IVT (OR=2.52 (95% CI 1.51 to 4.22); p<0.001) with better functional outcomes. There was a significantly lower 90-day mortality rate for patients who underwent bridging IVT compared with MT alone (RR=0.70 (95% CI 0.62 to 0.80); p=0.008). No significant differences were detected in rates of post-treatment recanalization (RR=1.01 (95% CI 0.35 to 2.91); p=0.954), sICH (RR=0.96 (95% CI 0.66 to 1.42); p=0.724), and SAH (RR=0.93 (95% CI 0.31 to 2.83); p=0.563).ConclusionsIn patients with AIS due to BAO, bridging IVT was associated with lower mortality rates at 90 days, compared with direct MT. There were no improved functional outcomes or increased sICH or SAH between both arms, However, patients with LAA benefited from bridging IVT, with better functional outcomes.
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| 46. |
- Myint, MZ, et al.
(author)
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Internal cerebral vein asymmetry is an independent predictor of poor functional outcome in endovascular thrombectomy
- 2022
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In: Journal of neurointerventional surgery. - : BMJ. - 1759-8486 .- 1759-8478. ; 14:7, s. 683-687
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Journal article (peer-reviewed)abstract
- Endovascular thrombectomy (EVT) in large vessel occlusion (LVO) in anterior circulation acute ischaemic stroke (AIS) results in good functional outcomes in only approximately 60% of the patients. Internal cerebral veins (ICVs) are easily visible, with a consistent midline location, and are linked to stroke outcomes. We hypothesize that ICV asymmetry on multiphasic CT angiogram (mCTA) can be an adjunctive predictor for poor functional outcomes.MethodsWe studied consecutive AIS patients from 2017 to 2019 with anterior circulation LVO treated with EVT regardless of intravenous thrombolysis. Asymmetrical ICV was defined as the presence of hypodensity (less opacification) on the ipsilateral occlusion side as compared with the contralateral side. The primary outcome was modified Rankin Score (mRS) score at 3 months. Secondary outcomes were good recanalization (modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3), symptomatic hemorrhage, and mortality.ResultsA total of 185 patients were included with a median age of 70 years (IQR 59–77); 87 patients (47%) were female. 82 patients (44.3%) achieved good functional outcomes (mRS 0–2) at 3 months. On multivariate analysis, National Institutes of Health Stroke Scale (NIHSS) (OR 1.076, 95% CI 1.015 to 1.140; p<0.013), poor collateral score (OR 0.285, 95% CI 0.162 to 0.501; p<0.001), asymmetrical ICV on the peak venous phase (OR 2.47, 95% CI 1.115 to 5.471; p<0.026), and late venous phase of the mCTA (OR 2.642, 95% CI 1.161 to 6.016; p<0.021) were independent risks factors of poor outcomes.ConclusionICV asymmetry is a novel radiological sign which is independently associated with poor functional outcomes in EVT, even after correction for collateral circulation. Further studies are needed to validate this finding.
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