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| 2. |
- Nik-Zainal, Serena, et al.
(författare)
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Landscape of somatic mutations in 560 breast cancer whole-genome sequences
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 534:7605, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
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| 4. |
- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 5. |
- Hammond, Philip S., et al.
(författare)
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Cetacean abundance and distribution in European Atlantic shelf waters to inform conservation and management
- 2013
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Ingår i: Biological Conservation. - : Elsevier BV. - 0006-3207 .- 1873-2917. ; 164, s. 107-122
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Tidskriftsartikel (refereegranskat)abstract
- The European Union (EU) Habitats Directive requires Member States to monitor and maintain at favourable conservation status those species identified to be in need of protection, including all cetaceans. In July 2005 we surveyed the entire EU Atlantic continental shelf to generate robust estimates of abundance for harbour porpoise and other cetacean species. The survey used line transect sampling methods and purpose built data collection equipment designed to minimise bias in estimates of abundance. Shipboard transects covered 19,725 km in sea conditions <= Beaufort 4 in an area of 1,005,743 km(2). Aerial transects covered 15,802 km in good/moderate conditions (<= Beaufort 3) in an area of 364,371 km(2). Thirteen cetacean species were recorded; abundance was estimated for harbour porpoise (375,358; CV = 0.197), bottlenose dolphin (16,485; CV = 0.422), white-beaked dolphin (16,536; CV = 0.303), short-beaked common dolphin (56,221; CV = 0.234) and minke whale (18,958; CV = 0.347). Abundance in 2005 was similar to that estimated in July 1994 for harbour porpoise, white-beaked dolphin and minke whale in a comparable area. However, model-based density surfaces showed a marked difference in harbour porpoise distribution between 1994 and 2005. Our results allow EU Member States to discharge their responsibilities under the Habitats Directive and inform other international organisations concerning the assessment of conservation status of cetaceans and the impact of bycatch at a large spatial scale. The lack of evidence for a change in harbour porpoise abundance in EU waters as a whole does not exclude the possibility of an impact of bycatch in some areas. Monitoring bycatch and estimation of abundance continue to be essential. (C) 2013 The Authors.
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| 6. |
- Haupt, Riccardo, et al.
(författare)
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The ‘Survivorship Passport’ for childhood cancer survivors
- 2018
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049. ; 102, s. 69-81
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Tidskriftsartikel (refereegranskat)abstract
- Background: Currently, there are between 300,000 and 500,000 childhood cancer survivors (CCSs) in Europe. A significant proportion is at high risk, and at least 60% of them develop adverse health-related outcomes that can appear several years after treatment completion. Many survivors are unaware of their personal risk, and there seems to be a general lack of information among healthcare providers about pathophysiology and natural history of treatment-related complications. This can generate incorrect or delayed diagnosis and treatments. Method: The Survivorship Passport (SurPass) consists of electronic documents, which summarise the clinical history of the childhood or adolescent cancer survivor. It was developed by paediatric oncologists of the PanCare and SIOPE networks and IT experts of Cineca, together with parents, patients, and survivors’ organisations within the European Union–funded European Network for Cancer research in Children and Adolescents. It consists of a template of a web-based, simply written document, translatable in all European languages, to be given to each CCS. The SurPass provides a summary of each survivor's clinical history, with detailed information about the original cancer and of treatments received, together with personalised follow-up and screening recommendations based on guidelines published by the International Guidelines Harmonization Group and PanCareSurFup. Results: The SurPass data schema contains a maximum of 168 variables and uses internationally approved nomenclature, except for radiotherapy fields, where a new classification was defined by radiotherapy experts. The survivor-specific screening recommendations are mainly based on treatment received and are automatically suggested, thanks to built-in algorithms. These may be adapted and further individualised by the treating physician in case of special disease and survivor circumstances. The SurPass was tested at the Istituto Giannina Gaslini, Italy, and received positive feedback. It is now being integrated at the institutional, regional and national level. Conclusions: The SurPass is potentially an essential tool for improved and more harmonised follow-up of CCS. It also has the potential to be a useful tool for empowering CCSs to be responsible for their own well-being and preventing adverse events whenever possible. With sufficient commitment on the European level, this solution should increase the capacity to respond more effectively to the needs of European CCS.
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| 7. |
- Nik-Zainal, Serena, et al.
(författare)
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Mutational Processes Molding the Genomes of 21 Breast Cancers
- 2012
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5, s. 979-993
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Tidskriftsartikel (refereegranskat)abstract
- All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis,'' was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.
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| 8. |
- Nik-Zainal, Serena, et al.
(författare)
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The Life History of 21 Breast Cancers
- 2012
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5
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Tidskriftsartikel (refereegranskat)abstract
- Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
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| 9. |
- Owen, Kylie, et al.
(författare)
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A negative trend in abundance and an exceeded mortality limit call for conservation action for the Vulnerable Belt Sea harbour porpoise population
- 2024
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Ingår i: Frontiers in Marine Science. - 2296-7745. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The management and conservation of biodiversity relies on information on both the abundance of species and the potential impact of threats. Globally, one of the largest threats towards marine biodiversity is bycatch in fisheries. Under the Marine Strategy Framework Directive (MSFD), EU Member States are required to assess the status of species, such as the harbour porpoise (Phocoena phocoena), in relation to their abundance and mortality due to bycatch every six years. The Vulnerable (HELCOM) Belt Sea population of harbour porpoise has been surveyed to determine its abundance six times using dedicated aerial or ship-based line-transect distance sampling surveys. Here, we estimated the first trend in population abundance over an 18 year period (2005-2022). Using the most recent abundance estimate, we computed a mortality limit applying the modified Potential Biological Removal (mPBR) method based on the regionally agreed conservation objective to restore or maintain 80% of carrying capacity over 100 years with an 80% probability. Over the past 18 years there has been a strong negative trend (-2.7% p.a.; 95% CI: -4.1%; + 1.3%) in abundance, with a 90.5% probability. The mortality limit was estimated to be 24 animals, which the current bycatch estimates (similar to 900 porpoises/year from the commercial Danish and Swedish set net fishery fleets, with no data from Germany and other fishery types) exceed by far. The frequency and quality of data available on abundance for this population are higher than those available for the majority of marine species. Given the observed population decline and likely unsustainable levels of bycatch, the results presented here provide a strong basis to make informed, evidence-based management decisions for action for this population. Such action is needed urgently, before the dire situation of other porpoise species and populations around the globe is repeated.
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| 10. |
- Shlien, Adam, et al.
(författare)
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Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 16:7, s. 2032-2046
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Tidskriftsartikel (refereegranskat)abstract
- Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we integrated with whole genomes from 23 breast cancers. Using X-inactivation analyses, we found that cancer cells are more transcriptionally active than intermixed stromal cells. This is especially true in estrogen receptor (ER)-negative tumors. Overall, 59% of substitutions were expressed. Nonsense mutations showed lower expression levels than expected, with patterns characteristic of nonsense-mediated decay. 14% of 4,234 rearrangements caused transcriptional abnormalities, including exon skips, exon reusage, fusions, and premature polyadenylation. We found productive, stable transcription from sense-to-antisense gene fusions and gene-to-intergenic rearrangements, suggesting that these mutation classes drive more transcriptional disruption than previously suspected. Systematic integration of transcriptome with genome data reveals the rules by which transcriptional machinery interprets somatic mutation.
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