ALBERT

Description: Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137369/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137369/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Campbell, Peter J -- Yachida, Shinichi -- Mudie, Laura J -- Stephens, Philip J -- Pleasance, Erin D -- Stebbings, Lucy A -- Morsberger, Laura A -- Latimer, Calli -- McLaren, Stuart -- Lin, Meng-Lay -- McBride, David J -- Varela, Ignacio -- Nik-Zainal, Serena A -- Leroy, Catherine -- Jia, Mingming -- Menzies, Andrew -- Butler, Adam P -- Teague, Jon W -- Griffin, Constance A -- Burton, John -- Swerdlow, Harold -- Quail, Michael A -- Stratton, Michael R -- Iacobuzio-Donahue, Christine -- Futreal, P Andrew -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- CA106610/CA/NCI NIH HHS/ -- CA140599/CA/NCI NIH HHS/ -- K08 CA106610/CA/NCI NIH HHS/ -- K08 CA106610-03/CA/NCI NIH HHS/ -- K08 CA106610-04/CA/NCI NIH HHS/ -- K08 CA106610-05/CA/NCI NIH HHS/ -- R01 CA140599/CA/NCI NIH HHS/ -- R01 CA140599-01/CA/NCI NIH HHS/ -- R01 CA140599-02/CA/NCI NIH HHS/ -- R01 CA140599-03/CA/NCI NIH HHS/ -- WT088340MA/Wellcome Trust/United Kingdom -- England -- Nature. 2010 Oct 28;467(7319):1109-13. doi: 10.1038/nature09460.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20981101" target="_blank"〉PubMed〈/a〉

Description: Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3' transduction. Because 3' transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3' transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3' transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3' transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380235/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380235/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tubio, Jose M C -- Li, Yilong -- Ju, Young Seok -- Martincorena, Inigo -- Cooke, Susanna L -- Tojo, Marta -- Gundem, Gunes -- Pipinikas, Christodoulos P -- Zamora, Jorge -- Raine, Keiran -- Menzies, Andrew -- Roman-Garcia, Pablo -- Fullam, Anthony -- Gerstung, Moritz -- Shlien, Adam -- Tarpey, Patrick S -- Papaemmanuil, Elli -- Knappskog, Stian -- Van Loo, Peter -- Ramakrishna, Manasa -- Davies, Helen R -- Marshall, John -- Wedge, David C -- Teague, Jon W -- Butler, Adam P -- Nik-Zainal, Serena -- Alexandrov, Ludmil -- Behjati, Sam -- Yates, Lucy R -- Bolli, Niccolo -- Mudie, Laura -- Hardy, Claire -- Martin, Sancha -- McLaren, Stuart -- O'Meara, Sarah -- Anderson, Elizabeth -- Maddison, Mark -- Gamble, Stephen -- ICGC Breast Cancer Group -- ICGC Bone Cancer Group -- ICGC Prostate Cancer Group -- Foster, Christopher -- Warren, Anne Y -- Whitaker, Hayley -- Brewer, Daniel -- Eeles, Rosalind -- Cooper, Colin -- Neal, David -- Lynch, Andy G -- Visakorpi, Tapio -- Isaacs, William B -- van't Veer, Laura -- Caldas, Carlos -- Desmedt, Christine -- Sotiriou, Christos -- Aparicio, Sam -- Foekens, John A -- Eyfjord, Jorunn Erla -- Lakhani, Sunil R -- Thomas, Gilles -- Myklebost, Ola -- Span, Paul N -- Borresen-Dale, Anne-Lise -- Richardson, Andrea L -- Van de Vijver, Marc -- Vincent-Salomon, Anne -- Van den Eynden, Gert G -- Flanagan, Adrienne M -- Futreal, P Andrew -- Janes, Sam M -- Bova, G Steven -- Stratton, Michael R -- McDermott, Ultan -- Campbell, Peter J -- 088340/Wellcome Trust/United Kingdom -- 091730/Wellcome Trust/United Kingdom -- 14835/Cancer Research UK/United Kingdom -- C5047/A14835/Cancer Research UK/United Kingdom -- G0900871/Medical Research Council/United Kingdom -- P30 CA006973/CA/NCI NIH HHS/ -- WT100183MA/Wellcome Trust/United Kingdom -- Department of Health/United Kingdom -- New York, N.Y. -- Science. 2014 Aug 1;345(6196):1251343. doi: 10.1126/science.1251343.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. ; Department of Physiology, School of Medicine-Center for Resesarch in Molecular Medicine and Chronic Diseases, Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, Spain. ; Lungs for Living Research Centre, Rayne Institute, University College London (UCL), London, UK. ; Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. Department of Clinical Science, University of Bergen, Bergen, Norway. Department of Oncology, Haukeland University Hospital, Bergen, Norway. ; Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium. ; Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK. ; Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. Department of Haematology, University of Cambridge, Cambridge, UK. ; University of Liverpool and HCA Pathology Laboratories, London, UK. ; Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK. ; Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge, UK. ; Institute of Cancer Research, Sutton, London, UK. University of East Anglia, Norwich, UK. ; Institute of Cancer Research, Sutton, London, UK. ; Institute of Biosciences and Medical Technology-BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland. ; Johns Hopkins University, Baltimore, MD, USA. ; Netherlands Cancer Institute, Amsterdam, Netherlands. ; Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. ; British Columbia Cancer Agency, Vancouver, Canada. ; Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands. ; Cancer Research Laboratory, University of Iceland, Reykjavik, Iceland. ; School of Medicine, University of Queensland, Brisbane, Australia. Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia. UQ Centre for Clinical Research, University of Queensland, Brisbane, Australia. ; Universite Lyon 1, Institut National du Cancer (INCa)-Synergie, Lyon, France. ; Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. ; Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands. ; Dana-Farber Cancer Institute, Boston, MA, USA. ; Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. ; Institut Bergonie, 229 cours de l'Argone, 33076 Bordeaux, France. Institut Curie, Department of Tumor Biology, 26 rue d'Ulm, 75248 Paris cedex 05, France. ; Translational Cancer Research Unit and Department of Pathology, GZA Hospitals, Antwerp, Belgium. ; Royal National Orthopaedic Hospital, Middlesex, UK. UCL Cancer Institute, University College London, London, UK. ; Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. MD Anderson Cancer Center, Houston, TX, USA. ; Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. pc8@sanger.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25082706" target="_blank"〉PubMed〈/a〉

Description: The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145113/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145113/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bignell, Graham R -- Greenman, Chris D -- Davies, Helen -- Butler, Adam P -- Edkins, Sarah -- Andrews, Jenny M -- Buck, Gemma -- Chen, Lina -- Beare, David -- Latimer, Calli -- Widaa, Sara -- Hinton, Jonathon -- Fahey, Ciara -- Fu, Beiyuan -- Swamy, Sajani -- Dalgliesh, Gillian L -- Teh, Bin T -- Deloukas, Panos -- Yang, Fengtang -- Campbell, Peter J -- Futreal, P Andrew -- Stratton, Michael R -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- P01 CA155258/CA/NCI NIH HHS/ -- England -- Nature. 2010 Feb 18;463(7283):893-8. doi: 10.1038/nature08768.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164919" target="_blank"〉PubMed〈/a〉

Description: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776390/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776390/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alexandrov, Ludmil B -- Nik-Zainal, Serena -- Wedge, David C -- Aparicio, Samuel A J R -- Behjati, Sam -- Biankin, Andrew V -- Bignell, Graham R -- Bolli, Niccolo -- Borg, Ake -- Borresen-Dale, Anne-Lise -- Boyault, Sandrine -- Burkhardt, Birgit -- Butler, Adam P -- Caldas, Carlos -- Davies, Helen R -- Desmedt, Christine -- Eils, Roland -- Eyfjord, Jorunn Erla -- Foekens, John A -- Greaves, Mel -- Hosoda, Fumie -- Hutter, Barbara -- Ilicic, Tomislav -- Imbeaud, Sandrine -- Imielinski, Marcin -- Jager, Natalie -- Jones, David T W -- Jones, David -- Knappskog, Stian -- Kool, Marcel -- Lakhani, Sunil R -- Lopez-Otin, Carlos -- Martin, Sancha -- Munshi, Nikhil C -- Nakamura, Hiromi -- Northcott, Paul A -- Pajic, Marina -- Papaemmanuil, Elli -- Paradiso, Angelo -- Pearson, John V -- Puente, Xose S -- Raine, Keiran -- Ramakrishna, Manasa -- Richardson, Andrea L -- Richter, Julia -- Rosenstiel, Philip -- Schlesner, Matthias -- Schumacher, Ton N -- Span, Paul N -- Teague, Jon W -- Totoki, Yasushi -- Tutt, Andrew N J -- Valdes-Mas, Rafael -- van Buuren, Marit M -- van 't Veer, Laura -- Vincent-Salomon, Anne -- Waddell, Nicola -- Yates, Lucy R -- Australian Pancreatic Cancer Genome Initiative -- ICGC Breast Cancer Consortium -- ICGC MMML-Seq Consortium -- ICGC PedBrain -- Zucman-Rossi, Jessica -- Futreal, P Andrew -- McDermott, Ultan -- Lichter, Peter -- Meyerson, Matthew -- Grimmond, Sean M -- Siebert, Reiner -- Campo, Elias -- Shibata, Tatsuhiro -- Pfister, Stefan M -- Campbell, Peter J -- Stratton, Michael R -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- T32 CA009216/CA/NCI NIH HHS/ -- England -- Nature. 2013 Aug 22;500(7463):415-21. doi: 10.1038/nature12477. Epub 2013 Aug 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23945592" target="_blank"〉PubMed〈/a〉

Description: Worldwide, there is growing recognition of the need to reduce agricultural groundwater use in response to rapid rates of aquifer depletion. To date, however, few studies have evaluated how benefits of conservation vary along an aquifer's depletion pathway. To address this question, we develop an integrated modeling framework that couples an agro-economic model of farmers' field-level irrigation decision-making with a borehole-scale groundwater flow model. Unique to this framework is the explicit consideration of the dynamic reductions in well yields that occur as an aquifer is depleted, and how these changes in intraseasonal groundwater supply affect farmers' ability to manage production risks caused by climate variability and, in particular, drought. For an illustrative case study in the High Plains region of the United States, we apply our model to analyze the value of groundwater conservation activities for different initial aquifer conditions. Our results demonstrate that there is a range of initial conditions for which reducing pumping will have long-term economic benefits for farmers by slowing reductions in well yields and prolonging the usable lifetime of an aquifer for high-value irrigated agriculture. In contrast, restrictions on pumping that are applied too early or too late will provide limited welfare benefits. We suggest, therefore, that there are ‘windows of opportunity’ to implement groundwater conservation, which will depend on complex feedbacks between local hydrology, climate, crop growth, and economics. This article is protected by copyright. All rights reserved.

Description: Long-term surface and borehole self-potential (SP) monitoring was conducted in the UK Chalk aquifer at two sites. The coastal site is c. 1.7 km from the coast and the inland site is c. 80 km from the coast. At both sites, power spectral density analysis revealed that SP data contain the main ocean tidal periodic components. However, the principal lunar component (M 2 ), the dominant ocean tidal component, was most significant at the coastal site. The M 2 signal in surface-referenced SP data at the inland site was partly due to telluric currents caused by the geomagnetic ocean dynamo. Earth and/or atmospheric tides also contributed, as the SP power spectrum was not typical of a telluric electric field. The M 2 component in borehole-referenced data at the inland site was below the significance level of the analysis method and was two orders of magnitude smaller than the M 2 signal in borehole-referenced SP data at the coastal site. The tidal response of the SP data in the coastal borehole is, therefore, primarily driven by ocean tides. These cause changes in fluid pressure and chemical concentration gradients within the coastal aquifer, leading to time varying electrokinetic and exclusion-diffusion potentials. Borehole-referenced SP measurements could be used to characterize and monitor tidal processes in coastal aquifers such as the intrusion of seawater.