| 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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| 3. |
- Aguiar, A., et al.
(författare)
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Practices in prescribing protein substitutes for PKU in Europe : No uniformity of approach
- 2015
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192 .- 1096-7206. ; 115:1, s. 17-22
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Tidskriftsartikel (refereegranskat)abstract
- Background: There appears little consensus concerning protein requirements in phenylketonuria (PKU). Methods: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics. Results: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n = 24 centres) (infants <1 year, >2-3 g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n = 10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n = 4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n = 25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day). Conclusions: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.
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| 5. |
- Kurilshikov, Alexander, et al.
(författare)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 7. |
- Wang, Yifan, et al.
(författare)
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The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin
- 2016
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Ingår i: Cancer Research. - 0008-5472. ; 76:9, s. 2778-2790
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Tidskriftsartikel (refereegranskat)abstract
- Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1- Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance.
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| 11. |
- Eijsbouts, C., et al.
(författare)
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Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53:11, s. 1543-1552
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS. © 2021, The Author(s).
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| 13. |
- Hiesmayr, M., et al.
(författare)
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Decreased food intake is a risk factor for mortality in hospitalised patients : the NutritionDay survey 2006
- 2009
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Ingår i: Clinical Nutrition. - : Elsevier BV. - 0261-5614 .- 1532-1983. ; 28:5, s. 484-491
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Malnutrition is a known risk factor for the development of complications in hospitalised patients. We determined whether eating only fractions of the meals served is an independent risk factor for mortality. METHODS: The NutritionDay is a multinational one-day cross-sectional survey of nutritional factors and food intake in 16,290 adult hospitalised patients on January 19th 2006. The effect of food intake and nutritional factors on death in hospital within 30 days was assessed in a competing risk analysis. RESULTS: More than half of the patients did not eat their full meal provided by the hospital. Decreased food intake on NutritionDay or during the previous week was associated with an increased risk of dying, even after adjustment for various patient and disease related factors. Adjusted hazard ratio for dying when eating about a quarter of the meal on NutritionDay was 2.10 (1.53-2.89); when eating nothing 3.02 (2.11-4.32). More than half of the patients who ate less than a quarter of their meal did not receive artificial nutrition support. Only 25% patients eating nothing at lunch receive artificial nutrition support. CONCLUSION: Many hospitalised patients in European hospitals eat less food than provided as regular meal. This decreased food intake represents an independent risk factor for hospital mortality.
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| 18. |
- Prins, Jonne T H, et al.
(författare)
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Surgical stabilization of rib fractures versus nonoperative treatment in patients with multiple rib fractures following cardiopulmonary resuscitation: An international, retrospective matched case-control study.
- 2022
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Ingår i: The journal of trauma and acute care surgery. - 2163-0763. ; 93:6, s. 727-735
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Tidskriftsartikel (refereegranskat)abstract
- The presence of six or more rib fractures or a displaced rib fracture due to cardiopulmonary resuscitation (CPR) has been associated with longer hospital and intensive care unit (ICU) length of stay (LOS). Evidence on the effect of surgical stabilization of rib fractures (SSRF) following CPR is limited. This study aimed to evaluate outcomes after SSRF versus nonoperative management in patients with multiple rib fractures after CPR.An international, retrospective study was performed in patients who underwent SSRF or nonoperative management for multiple rib fractures following CPR between January 1, 2012, and July 31, 2020. Patients who underwent SSRF were matched to nonoperative controls by cardiac arrest location and cause, rib fracture pattern, and age. The primary outcome was ICU LOS.Thirty-nine operatively treated patient were matched to 66 nonoperatively managed controls with comparable CPR-related characteristics. Patients who underwent SSRF more often had displaced rib fractures (n = 28 [72%] vs. n = 31 [47%]; p = 0.015) and a higher median number of displaced ribs (2 [P 25 -P 75 , 0-3] vs. 0 [P 25 -P 75 , 0-3]; p = 0.014). Surgical stabilization of rib fractures was performed at a median of 5 days (P 25 -P 75 , 3-8 days) after CPR. In the nonoperative group, a rib fixation specialist was consulted in 14 patients (21%). The ICU LOS was longer in the SSRF group (13 days [P 25 -P 75 , 9-23 days] vs. 9 days [P 25 -P 75 , 5-15 days]; p = 0.004). Mechanical ventilator-free days, hospital LOS, thoracic complications, and mortality were similar.Despite matching, those who underwent SSRF over nonoperative management for multiple rib fractures following CPR had more severe consequential chest wall injury and a longer ICU LOS. A benefit of SSRF on in-hospital outcomes could not be demonstrated. A low consultation rate for rib fixation in the nonoperative group indicates that the consideration to perform SSRF in this population might be associated with other nonradiographic or injury-related variables.Therapeutic/Care Management; Level III.
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