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  • 1
    Keywords: PROSTATE-CANCER ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; SQUAMOUS-CELL CARCINOMA ; LUNG ADENOCARCINOMA ; ACUTE MYELOID-LEUKEMIA ; SOMATIC MUTATIONS ; GENETIC LANDSCAPE ; 21 BREAST CANCERS ; RECURRENT MUTATIONS ; FREQUENT MUTATION
    Abstract: 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.
    Type of Publication: Journal article published
    PubMed ID: 23945592
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  • 2
    Abstract: The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.
    Type of Publication: Journal article published
    PubMed ID: 27121471
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  • 3
    Publication Date: 2018-08-10
    Description: Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1 , IDH2 , HUWE1 , KLHL6 , and PTPN11 . Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3 , DIS3 , and PRKD2 ; t(11;14) with mutations in CCND1 and IRF4 ; t(14;16) with mutations in MAF , BRAF , DIS3 , and ATM ; and hyperdiploidy with gain 11q, mutations in FAM46C , and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.
    Keywords: Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2013-08-16
    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〉
    Keywords: Aging/genetics ; Algorithms ; Cell Transformation, Neoplastic/*genetics/pathology ; Cytidine Deaminase/genetics ; DNA/genetics/metabolism ; DNA Mutational Analysis ; Humans ; Models, Genetic ; Mutagenesis/*genetics ; Mutagenesis, Insertional/genetics ; Mutagens/pharmacology ; Mutation/*genetics ; Neoplasms/enzymology/*genetics/pathology ; Organ Specificity ; Reproducibility of Results ; Sequence Deletion/genetics ; Transcription, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2014-08-02
    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〉
    Keywords: Carcinogenesis/genetics ; Chromatin/chemistry ; *DNA Transposable Elements ; Exons ; Genome, Human ; Humans ; *Long Interspersed Nucleotide Elements ; Mutagenesis, Insertional ; Neoplasms/*genetics ; *Transduction, Genetic ; Translocation, Genetic
    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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