Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Publication Date: 2014-11-05
    Description: Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor in mouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) Kras Q61L mutations, indicating a major role for germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C 〉 T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304785/" 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/PMC4304785/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Westcott, Peter M K -- Halliwill, Kyle D -- To, Minh D -- Rashid, Mamunur -- Rust, Alistair G -- Keane, Thomas M -- Delrosario, Reyno -- Jen, Kuang-Yu -- Gurley, Kay E -- Kemp, Christopher J -- Fredlund, Erik -- Quigley, David A -- Adams, David J -- Balmain, Allan -- 082356/Wellcome Trust/United Kingdom -- 13031/Cancer Research UK/United Kingdom -- A12401/Cancer Research UK/United Kingdom -- A13031/Cancer Research UK/United Kingdom -- A14356/Cancer Research UK/United Kingdom -- F31 CA180669/CA/NCI NIH HHS/ -- F31 CA180715/CA/NCI NIH HHS/ -- R01 CA111834/CA/NCI NIH HHS/ -- R01 CA184510/CA/NCI NIH HHS/ -- T32 GM007175/GM/NIGMS NIH HHS/ -- T32GM007175/GM/NIGMS NIH HHS/ -- U01 CA084244/CA/NCI NIH HHS/ -- U01 CA141455/CA/NCI NIH HHS/ -- U01 CA176287/CA/NCI NIH HHS/ -- U01 CA84244/CA/NCI NIH HHS/ -- UO1 CA176287/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2015 Jan 22;517(7535):489-92. doi: 10.1038/nature13898. Epub 2014 Nov 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA [2] Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94158, USA. ; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA. ; Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK. ; Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, Stockholm 171 21, Sweden. ; 1] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA [2] Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363767" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/chemically induced/genetics ; Animals ; Carcinogens/toxicity ; Carcinoma, Non-Small-Cell Lung/chemically induced/genetics ; Cell Transformation, Neoplastic/*chemically induced/*genetics ; DNA Copy Number Variations/genetics ; Disease Progression ; Female ; Genes, ras/*genetics ; Genomic Instability/genetics ; Germ-Line Mutation/genetics ; Humans ; Lung Neoplasms/*chemically induced/*genetics ; Male ; Methylnitrosourea/toxicity ; Mice ; Models, Genetic ; Mutation/*genetics ; Oncogene Protein p21(ras)/*genetics ; Point Mutation/genetics ; Proto-Oncogene Proteins p21(ras)/*genetics ; Urethane/toxicity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Publication Date: 2011-09-17
    Description: Structural variation is widespread in mammalian genomes and is an important cause of disease, but just how abundant and important structural variants (SVs) are in shaping phenotypic variation remains unclear. Without knowing how many SVs there are, and how they arise, it is difficult to discover what they do. Combining experimental with automated analyses, we identified 711,920 SVs at 281,243 sites in the genomes of thirteen classical and four wild-derived inbred mouse strains. The majority of SVs are less than 1 kilobase in size and 98% are deletions or insertions. The breakpoints of 160,000 SVs were mapped to base pair resolution, allowing us to infer that insertion of retrotransposons causes more than half of SVs. Yet, despite their prevalence, SVs are less likely than other sequence variants to cause gene expression or quantitative phenotypic variation. We identified 24 SVs that disrupt coding exons, acting as rare variants of large effect on gene function. One-third of the genes so affected have immunological functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428933/" 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/PMC3428933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yalcin, Binnaz -- Wong, Kim -- Agam, Avigail -- Goodson, Martin -- Keane, Thomas M -- Gan, Xiangchao -- Nellaker, Christoffer -- Goodstadt, Leo -- Nicod, Jerome -- Bhomra, Amarjit -- Hernandez-Pliego, Polinka -- Whitley, Helen -- Cleak, James -- Dutton, Rebekah -- Janowitz, Deborah -- Mott, Richard -- Adams, David J -- Flint, Jonathan -- 079912/Wellcome Trust/United Kingdom -- 082356/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 13031/Cancer Research UK/United Kingdom -- G0800024/Medical Research Council/United Kingdom -- MC_U137761446/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 Sep 14;477(7364):326-9. doi: 10.1038/nature10432.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21921916" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromosome Breakpoints ; Exons/genetics ; Female ; Gene Expression ; Genetic Variation/*genetics ; Genome/*genetics ; Genomics ; Genotype ; Male ; Mice ; Mice, Inbred Strains/*genetics/immunology ; Mutagenesis, Insertional/genetics ; *Phenotype ; Quantitative Trait Loci/genetics ; Rats ; Retroelements/genetics ; Sequence Deletion/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Publication Date: 2011-09-17
    Description: We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276836/" 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/PMC3276836/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keane, Thomas M -- Goodstadt, Leo -- Danecek, Petr -- White, Michael A -- Wong, Kim -- Yalcin, Binnaz -- Heger, Andreas -- Agam, Avigail -- Slater, Guy -- Goodson, Martin -- Furlotte, Nicholas A -- Eskin, Eleazar -- Nellaker, Christoffer -- Whitley, Helen -- Cleak, James -- Janowitz, Deborah -- Hernandez-Pliego, Polinka -- Edwards, Andrew -- Belgard, T Grant -- Oliver, Peter L -- McIntyre, Rebecca E -- Bhomra, Amarjit -- Nicod, Jerome -- Gan, Xiangchao -- Yuan, Wei -- van der Weyden, Louise -- Steward, Charles A -- Bala, Sendu -- Stalker, Jim -- Mott, Richard -- Durbin, Richard -- Jackson, Ian J -- Czechanski, Anne -- Guerra-Assuncao, Jose Afonso -- Donahue, Leah Rae -- Reinholdt, Laura G -- Payseur, Bret A -- Ponting, Chris P -- Birney, Ewan -- Flint, Jonathan -- Adams, David J -- 077192/Wellcome Trust/United Kingdom -- 079912/Wellcome Trust/United Kingdom -- 082356/Wellcome Trust/United Kingdom -- 083573/Wellcome Trust/United Kingdom -- 083573/Z/07/Z/Wellcome Trust/United Kingdom -- 085906/Wellcome Trust/United Kingdom -- 085906/Z/08/Z/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 2T15LM007359/LM/NLM NIH HHS/ -- A6997/Cancer Research UK/United Kingdom -- BB/F022697/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- G0800024/Medical Research Council/United Kingdom -- K25 HL080079/HL/NHLBI NIH HHS/ -- MC_U127561112/Medical Research Council/United Kingdom -- MC_U137761446/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2011 Sep 14;477(7364):289-94. doi: 10.1038/nature10413.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21921910" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Animals, Laboratory/genetics ; Gene Expression Regulation/*genetics ; Genetic Variation/*genetics ; Genome/*genetics ; Genomics ; Mice/classification/*genetics ; Mice, Inbred C57BL/genetics ; Mice, Inbred Strains/*genetics ; *Phenotype ; Phylogeny ; Quantitative Trait Loci/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...