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  • 1
    Publication Date: 2013-03-01
    Description: Cancer chromosomal instability (CIN) results in an increased rate of change of chromosome number and structure and generates intratumour heterogeneity. CIN is observed in most solid tumours and is associated with both poor prognosis and drug resistance. Understanding a mechanistic basis for CIN is therefore paramount. Here we find evidence for impaired replication fork progression and increased DNA replication stress in CIN(+) colorectal cancer (CRC) cells relative to CIN(-) CRC cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. We identify three new CIN-suppressor genes (PIGN (also known as MCD4), MEX3C (RKHD2) and ZNF516 (KIAA0222)) encoded on chromosome 18q that are subject to frequent copy number loss in CIN(+) CRC. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN-suppressor gene silencing leads to DNA replication stress, structural chromosome abnormalities and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage, reduces the frequency of chromosome segregation errors after CIN-suppressor gene silencing, and attenuates segregation errors and DNA damage in CIN(+) cells. These data implicate a central role for replication stress in the generation of structural and numerical CIN, which may inform new therapeutic approaches to limit intratumour heterogeneity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636055/" 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/PMC4636055/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burrell, Rebecca A -- McClelland, Sarah E -- Endesfelder, David -- Groth, Petra -- Weller, Marie-Christine -- Shaikh, Nadeem -- Domingo, Enric -- Kanu, Nnennaya -- Dewhurst, Sally M -- Gronroos, Eva -- Chew, Su Kit -- Rowan, Andrew J -- Schenk, Arne -- Sheffer, Michal -- Howell, Michael -- Kschischo, Maik -- Behrens, Axel -- Helleday, Thomas -- Bartek, Jiri -- Tomlinson, Ian P -- Swanton, Charles -- 090532/Wellcome Trust/United Kingdom -- A11590/Cancer Research UK/United Kingdom -- A17786/Cancer Research UK/United Kingdom -- A19310/Cancer Research UK/United Kingdom -- A4688/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Feb 28;494(7438):492-6. doi: 10.1038/nature11935.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23446422" target="_blank"〉PubMed〈/a〉
    Keywords: Aneuploidy ; Cell Line, Tumor ; Chromosomal Instability/drug effects/*genetics ; Chromosome Segregation/drug effects/genetics ; Chromosomes, Human, Pair 18/drug effects/genetics ; Colorectal Neoplasms/*genetics/pathology ; DNA Copy Number Variations/genetics ; DNA Damage/drug effects/genetics ; DNA Replication/drug effects/*genetics ; Gene Deletion ; Gene Silencing ; Genes, Tumor Suppressor ; Humans ; Mitosis/drug effects ; Nucleosides/pharmacology ; Phosphotransferases/genetics ; RNA-Binding Proteins/genetics
    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: 2014-10-11
    Description: Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636050/" 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/PMC4636050/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Bruin, Elza C -- McGranahan, Nicholas -- Mitter, Richard -- Salm, Max -- Wedge, David C -- Yates, Lucy -- Jamal-Hanjani, Mariam -- Shafi, Seema -- Murugaesu, Nirupa -- Rowan, Andrew J -- Gronroos, Eva -- Muhammad, Madiha A -- Horswell, Stuart -- Gerlinger, Marco -- Varela, Ignacio -- Jones, David -- Marshall, John -- Voet, Thierry -- Van Loo, Peter -- Rassl, Doris M -- Rintoul, Robert C -- Janes, Sam M -- Lee, Siow-Ming -- Forster, Martin -- Ahmad, Tanya -- Lawrence, David -- Falzon, Mary -- Capitanio, Arrigo -- Harkins, Timothy T -- Lee, Clarence C -- Tom, Warren -- Teefe, Enock -- Chen, Shann-Ching -- Begum, Sharmin -- Rabinowitz, Adam -- Phillimore, Benjamin -- Spencer-Dene, Bradley -- Stamp, Gordon -- Szallasi, Zoltan -- Matthews, Nik -- Stewart, Aengus -- Campbell, Peter -- Swanton, Charles -- 088340/Wellcome Trust/United Kingdom -- 091730/Wellcome Trust/United Kingdom -- 105104/Wellcome Trust/United Kingdom -- A11590/Cancer Research UK/United Kingdom -- A17786/Cancer Research UK/United Kingdom -- A19310/Cancer Research UK/United Kingdom -- A4688/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Oct 10;346(6206):251-6. doi: 10.1126/science.1253462.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Science and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. University of Cambridge, Cambridge CB2 1TN, UK. ; Instituto de Biomedicina y Biotecnologia de Cantabria (CSIC-UC-Sodercan), Departamento de Biologia Molecular, Universidad de Cantabria, Santander, Spain. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium. ; Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK. ; Lungs for Living Research Centre, University College London, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. University College London Hospitals, London NW1 2BU, UK. ; University College London Hospitals, London NW1 2BU, UK. ; Thermo Fisher Scientific, Carlsbad, CA 92008, USA. ; Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Children's Hospital Informatics Program, Harvard Medical School, Boston, MA 02115, USA. ; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. Cancer Research UK London Research Institute, London WC2A 3LY, UK. charles.swanton@cancer.org.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25301630" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinogens/toxicity ; Carcinoma, Non-Small-Cell Lung/chemically induced/*diagnosis/*genetics ; Cytidine Deaminase/genetics ; Evolution, Molecular ; Gene Dosage ; *Genetic Heterogeneity ; *Genomic Instability ; Humans ; Lung Neoplasms/chemically induced/*diagnosis/*genetics ; Mutation ; Neoplasm Recurrence, Local/genetics ; Prognosis ; Smoking/adverse effects ; Translocation, Genetic ; Tumor Cells, Cultured
    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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  • 3
    Publication Date: 2004-08-04
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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