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  • 1
    Publication Date: 2012-04-13
    Description: Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863681/" 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/PMC3863681/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Sohrab P -- Roth, Andrew -- Goya, Rodrigo -- Oloumi, Arusha -- Ha, Gavin -- Zhao, Yongjun -- Turashvili, Gulisa -- Ding, Jiarui -- Tse, Kane -- Haffari, Gholamreza -- Bashashati, Ali -- Prentice, Leah M -- Khattra, Jaswinder -- Burleigh, Angela -- Yap, Damian -- Bernard, Virginie -- McPherson, Andrew -- Shumansky, Karey -- Crisan, Anamaria -- Giuliany, Ryan -- Heravi-Moussavi, Alireza -- Rosner, Jamie -- Lai, Daniel -- Birol, Inanc -- Varhol, Richard -- Tam, Angela -- Dhalla, Noreen -- Zeng, Thomas -- Ma, Kevin -- Chan, Simon K -- Griffith, Malachi -- Moradian, Annie -- Cheng, S-W Grace -- Morin, Gregg B -- Watson, Peter -- Gelmon, Karen -- Chia, Stephen -- Chin, Suet-Feung -- Curtis, Christina -- Rueda, Oscar M -- Pharoah, Paul D -- Damaraju, Sambasivarao -- Mackey, John -- Hoon, Kelly -- Harkins, Timothy -- Tadigotla, Vasisht -- Sigaroudinia, Mahvash -- Gascard, Philippe -- Tlsty, Thea -- Costello, Joseph F -- Meyer, Irmtraud M -- Eaves, Connie J -- Wasserman, Wyeth W -- Jones, Steven -- Huntsman, David -- Hirst, Martin -- Caldas, Carlos -- Marra, Marco A -- Aparicio, Samuel -- 5U01ES017154-02/ES/NIEHS NIH HHS/ -- R01 GM084875/GM/NIGMS NIH HHS/ -- R01GM084875/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Apr 4;486(7403):395-9. doi: 10.1038/nature10933.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada. sshah@bccrc.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22495314" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Breast Neoplasms/diagnosis/*genetics/*pathology ; Clone Cells/metabolism/pathology ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; Disease Progression ; *Evolution, Molecular ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/genetics ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; INDEL Mutation/genetics ; Mutation/*genetics ; Point Mutation/genetics ; Precision Medicine ; Reproducibility of Results ; Sequence Analysis, RNA
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-05-07
    Description: MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1,302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy-number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA-mRNA interactions rather than as on-off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dvinge, Heidi -- Git, Anna -- Graf, Stefan -- Salmon-Divon, Mali -- Curtis, Christina -- Sottoriva, Andrea -- Zhao, Yongjun -- Hirst, Martin -- Armisen, Javier -- Miska, Eric A -- Chin, Suet-Feung -- Provenzano, Elena -- Turashvili, Gulisa -- Green, Andrew -- Ellis, Ian -- Aparicio, Sam -- Caldas, Carlos -- 11832/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 May 16;497(7449):378-82. doi: 10.1038/nature12108. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644459" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Breast Neoplasms/*genetics/pathology ; DNA Copy Number Variations ; Female ; Follow-Up Studies ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Genome, Human/genetics ; Humans ; Kaplan-Meier Estimate ; MicroRNAs/*genetics/metabolism ; Prognosis ; Proportional Hazards Models ; RNA, Messenger/genetics/metabolism ; RNA, Neoplasm/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-04-24
    Description: The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440846/" 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/PMC3440846/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Curtis, Christina -- Shah, Sohrab P -- Chin, Suet-Feung -- Turashvili, Gulisa -- Rueda, Oscar M -- Dunning, Mark J -- Speed, Doug -- Lynch, Andy G -- Samarajiwa, Shamith -- Yuan, Yinyin -- Graf, Stefan -- Ha, Gavin -- Haffari, Gholamreza -- Bashashati, Ali -- Russell, Roslin -- McKinney, Steven -- METABRIC Group -- Langerod, Anita -- Green, Andrew -- Provenzano, Elena -- Wishart, Gordon -- Pinder, Sarah -- Watson, Peter -- Markowetz, Florian -- Murphy, Leigh -- Ellis, Ian -- Purushotham, Arnie -- Borresen-Dale, Anne-Lise -- Brenton, James D -- Tavare, Simon -- Caldas, Carlos -- Aparicio, Samuel -- A7199/Cancer Research UK/United Kingdom -- P50HG02790/HG/NHGRI NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Apr 18;486(7403):346-52. doi: 10.1038/nature10983.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22522925" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/classification/diagnosis/*genetics/*pathology ; DNA Copy Number Variations/*genetics ; Female ; *Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks/genetics ; Genes, Neoplasm/genetics ; Genome, Human/*genetics ; Genomics ; Humans ; Kaplan-Meier Estimate ; MAP Kinase Kinase 4/genetics ; Polymorphism, Single Nucleotide/genetics ; Prognosis ; Protein Phosphatase 2/genetics ; Treatment Outcome
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-10-10
    Description: Characterizing genetic diversity in Africa is a crucial step for most analyses reconstructing the evolutionary history of anatomically modern humans. However, historic migrations from Eurasia into Africa have affected many contemporary populations, confounding inferences. Here, we present a 12.5x coverage ancient genome of an Ethiopian male ("Mota") who lived approximately 4500 years ago. We use this genome to demonstrate that the Eurasian backflow into Africa came from a population closely related to Early Neolithic farmers, who had colonized Europe 4000 years earlier. The extent of this backflow was much greater than previously reported, reaching all the way to Central, West, and Southern Africa, affecting even populations such as Yoruba and Mbuti, previously thought to be relatively unadmixed, who harbor 6 to 7% Eurasian ancestry.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gallego Llorente, M -- Jones, E R -- Eriksson, A -- Siska, V -- Arthur, K W -- Arthur, J W -- Curtis, M C -- Stock, J T -- Coltorti, M -- Pieruccini, P -- Stretton, S -- Brock, F -- Higham, T -- Park, Y -- Hofreiter, M -- Bradley, D G -- Bhak, J -- Pinhasi, R -- Manica, A -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Nov 13;350(6262):820-2. doi: 10.1126/science.aad2879. Epub 2015 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. mg632@cam.ac.uk joneser@tcd.ie ron.pinhasi@ucd.ie am315@cam.ac.uk. ; Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. mg632@cam.ac.uk joneser@tcd.ie ron.pinhasi@ucd.ie am315@cam.ac.uk. ; Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. Integrative Systems Biology Laboratory, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia. ; Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. ; Department of Society, Culture, and Language, University of South Florida St. Petersburg, 140 7th Avenue South, St. Petersburg, FL 33701, USA. ; Department of Anthropology, Ventura College, 4667 Telegraph Road, Ventura, CA 93003, USA. Humanities and Social Sciences Program, UCLA Extension, University of California Los Angeles, 10995 Le Conte Avenue, Los Angeles, CA 90095, USA. ; Department of Archaeology and Anthropology, University of Cambridge, Pembroke Street, Cambridge CB2 3QG, UK. ; Department of Physical Sciences, Earth and Environment, University of Siena, Via di Laterina, 8-53100 Siena, Italy. ; Department of Anthropology, University of Illinois at Urbana-Champaign, Public Service Archaeology and Architecture Program, 109 Davenport Hall, 607 South Mathews Avenue, Urbana, IL 61801, USA. ; Oxford Radiocarbon Accelerator Unit, Research Laboratory for Archaeology and the History of Art, University of Oxford, Dyson Perrins Building, South Parks Road, Oxford OX1 3QY, UK. Cranfield Forensic Institute, Cranfield University, Defence Academy of the United Kingdom, Shrivenham, Oxon SN6 8LA, UK. ; Oxford Radiocarbon Accelerator Unit, Research Laboratory for Archaeology and the History of Art, University of Oxford, Dyson Perrins Building, South Parks Road, Oxford OX1 3QY, UK. ; Theragen BiO Institute, 2nd Floor B-dong, AICT bldg, Iui-dong, Youngtong-gu, Suwon 443-270, Republic of Korea. ; Institute for Biochemistry and Biology, Faculty for Mathematics and Natural Sciences, University of Potsdam, Karl-Liebknechtstrasse 24-25, 14476 Potsdam Golm, Germany. Department of Biology, University of York, Wentworth Way, Heslington, York YO10 5DD, UK. ; Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. ; The Genomics Institute, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea. ; School of Archaeology and Earth Institute, University College Dublin, Dublin 4, Ireland. mg632@cam.ac.uk joneser@tcd.ie ron.pinhasi@ucd.ie am315@cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26449472" target="_blank"〉PubMed〈/a〉
    Keywords: African Continental Ancestry Group/*genetics ; Asia ; Biological Evolution ; Ethiopia ; Europe ; Genetic Variation ; *Genome, Human ; *Human Migration ; Humans ; Male
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    ISSN: 1432-2242
    Keywords: Translocation Double Heterozygote ; Aedes aegypti
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Two pure translocation homozygote stocks, T1/T1 and T3/T3, were used to produce a double translocation heterozygote system designated T1/T3, employing T1/T1 as the male and T3/T3 as the female parent. The double heterozygote showed 73 % sterility when mated to wild females. Tests on mating competitiveness, recombination frequency in the differential segment, insemination rate and inheritance of sterility after release, for four generations in laboratory cages, have been carried out to evaluate the efficiency of this strain as an agent for a population control programme.
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  • 6
    ISSN: 1432-2242
    Keywords: Emmer wheats ; Chromosome 1B ; C-Bands ; Seed storage protein genes ; Mapping
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Genetic mapping of polymorphic C-bands allows direct comparisons between genetic and physical maps. Eleven C-bands and two seed storage protein genes on chromosome 1B, polymorphic between Langdon durum and four accessions of T. dicoccoides, were used to study the distribution of recombination along the entire length of the chromosome. Recombination in the short arm was almost completely restricted to the satellite, two-thirds of the arm's length from the centromere; the Gli-B1 gene was found to be tightly linked to the telomeric C-band. In the long arm, the distal 51.4% of the arm accounted for 88% of recombination; the proximal half of the arm accounted for the remaining 12%. While the amount of crossing-over differed significantly between the four T. dicoccoides 1B chromosomes, there were no significant differences in the relative distributions of crossing-over along the chromosome. Consequently, the genetic maps obtained from the four individual T. dicoccoides chromosomes were combined to yield a consensus map of 14 markers (including the centromere) for the chromosome.
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  • 7
    ISSN: 1432-2242
    Keywords: Wheat ; Recombination ; Genetic mapping ; Interference
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Several studies have indicated a noncorrespondence between genetic and physical distances in wheat chromosomes. To study the physical distribution of recombination, polymorphism for C-banding patterns was used to monitor recombination in 67 segments in 11 B-genome chromosome arms of Triticum turgidum. Recombination was absent in proximal regions of all chromosome arms; its frequency increased exponentially with distance from the centromere. A significant difference was observed between the distribution of recombination in physically short and physically long arms. In physically short arms, recombination was almost exclusively concentrated in distal segments and only those regions were represented in their genetic maps. In physically long arms, while a majority of the genetic distance was again based upon recombination in distal chromosome segments, some interstitial recombination was observed. Consequently, these regions also contributed to the genetic maps. Such a pattern of recombination, skewed toward terminal segments of chromosomes, is probably a result of telomeric pairing initiation and strong positive chiasma interference. Interference averaged 0.81 in 35 pairs of adjacent segments and 0.57 across the entire recombining portions of chromosome arms. The total genetic map lengths of the arms corresponded closely to those expected on the basis of their metaphase-I chiasma frequencies. As a consequence of this uneven distribution of recombination there can be a 153-fold difference (or more) in the number of DNA base pairs per unit (centiMorgan) of genetic length.
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  • 8
    ISSN: 1432-0703
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Notes: Abstract This paper uses a six compartment environmental partitioning model to explore the transport and accumulation of pentachlorophenol (PCP) within and between various environmental media. Environmental concentrations were then used to estimate the amount of PCP entering the food chain and the long-term, average daily intake of PCP by the general population of the U.S. Results show that PCP partitions mainly into soil (96.5%) and that the food chain, especially fruits, vegetables, and grains, accounts for 99.9% of human exposure to PCP. The long-term, average daily intake of PCP is estimated to be 16 μg/day, which agrees well with a previous estimate of 19 μg/day (Geyeret al. 1987).
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  • 9
    ISSN: 1432-0703
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Notes: Abstract Octanol-water partition coefficients have been correlated with the bioaccumulation of organic chemicals in biological systems. It is demonstrated that the bioaccumulation of organics in human tissues was positively correlated with their octanol-water partition coefficients. The regression equations depicting this relationship were used to estimate the extent of past human exposure for the general population of the U.S. to organics for which measured background tissue concentrations are available. This technique provides an additional tool for evaluating the nature and extent of human exposure to environmental contaminants.
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  • 10
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 218 (1968), S. 368-369 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] After the releases, the behaviour of the set of translocation chromosomes (T) in the population would depend on their viability and on the relative frequency of the T and normal chromosomes. Fig. 1 (lower) shows the course of change of T frequency as a result of natural selection. A large ...
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