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      Landscape of somatic mutations in 560 breast cancer whole genome sequences

      1 , 2 , 1 , 3 , 1 , 1 , 1 , 1 , 1 , 4 , 5 , 1 , 1 , 1 , 6 , 1 , 7 , 8 , 9 , 10 , 11 , 11 , 12 , 10 , 11 , 3 , 13 , 14 , 15 , 16 , 1 , 17 , 18 , 1 , 19 , 7 , 1 , 20 , 21 , 1 , 22 , 23 , 24 , 21 , 25 , 1 , 1 , 1 , 1 , 1 , 26 , 27 , 28 , 1 , 1 , 7 , 29 , 7 , 30 , 1 , 1 , 31 , 1 , 32 , 33 , 18 , 34 , 18 , 34 , 35 , 1 , 36 , 16 , 37 , 38 , 39 , 40 , 41 , 42 , 16 , 3 , 24 , 17 , 43 , 44 , 1 , 45 , 1 , 46 , 18 , 30 , 47 , 31 , 24 , 48 , 9 , 8 , 20 , 7 , 10 , 11 , 15 , 19 , 22 , 44 , 1

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          We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

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          Is Open Access

          RCircos: an R package for Circos 2D track plots

          Background Circos is a Perl language based software package for visualizing similarities and differences of genome structure and positional relationships between genomic intervals. Running Circos requires extra data processing procedures to prepare plot data files and configure files from datasets, which limits its capability of integrating directly with other software tools such as R. Recently published R Bioconductor package ggbio provides a function to display genomic data in circular layout based on multiple other packages, which increases its complexity of usage and decreased the flexibility in integrating with other R pipelines. Results We implemented an R package, RCircos, using only R packages that come with R base installation. The package supports Circos 2D data track plots such as scatter, line, histogram, heatmap, tile, connectors, links, and text labels. Each plot is implemented with a specific function and input data for all functions are data frames which can be objects read from text files or generated with other R pipelines. Conclusion RCircos package provides a simple and flexible way to make Circos 2D track plots with R and could be easily integrated into other R data processing and graphic manipulation pipelines for presenting large-scale multi-sample genomic research data. It can also serve as a base tool to generate complex Circos images.
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            A small cell lung cancer genome reports complex tobacco exposure signatures

            SUMMARY Cancer is driven by mutation. Worldwide, tobacco smoking is the major lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. 22,910 somatic substitutions were identified, including 132 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in-frame, and another two lines carrying PVT1-CHD7 fusion genes, suggesting that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.
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              Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer

              Background: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). Methods: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. Results: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10−11). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10−5 and 10−29), and identified breast and pancreatic cell lines with BRCA defects. Conclusion: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.

                Author and article information

                11 June 2016
                2 May 2016
                2 May 2016
                02 November 2016
                : 534
                : 7605
                : 47-54
                [1 ]Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
                [2 ]East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK
                [3 ]Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
                [4 ]Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
                [5 ]Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
                [6 ]Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium
                [7 ]Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands
                [8 ]Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen, Netherlands
                [9 ]European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus,Hinxton, Cambridgeshire, CB10 1SD
                [10 ]Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital
                [11 ]K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
                [12 ]Department of Computer Science, University of Oslo, Oslo, Norway
                [13 ]Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea
                [14 ]Translational Research Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France
                [15 ]Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115 USA
                [16 ]The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
                [17 ]Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium
                [18 ]Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
                [19 ]Dana-Farber Cancer Institute, Boston, MA 02215 USA
                [20 ]Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
                [21 ]Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, South Korea
                [22 ]Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
                [23 ]Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, United States
                [24 ]Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030
                [25 ]Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea
                [26 ]Institut National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France
                [27 ]University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming, Besançon 25000, France
                [28 ]Pathology Department, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK
                [29 ]Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France
                [30 ]The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Australia
                [31 ]Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
                [32 ]IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy
                [33 ]Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France
                [34 ]Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium
                [35 ]Institut Curie, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France
                [36 ]Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom
                [37 ]Breast Cancer Now Toby Research Unit, King’s College London
                [38 ]Breast Cancer Now Toby Robin’s Research Centre, Institute of Cancer Research, London
                [39 ]Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
                [40 ]Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway
                [41 ]National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610
                [42 ]Singapore General Hospital, Outram Road, Singapore 169608
                [43 ]Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Av. de l’Europe, 38330 Montbonnot-Saint Martin, France
                [44 ]Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France
                [45 ]Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, 77230
                [46 ]Department of Radiation Oncology, and department of Laboratory Medicine, Radboud university medical center, Nijmegen, the Netherlands
                [47 ]Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane, Australia
                [48 ]Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street,Houston, Texas 77030
                Author notes
                Corresponding authors: Gu Kong ( gkong@ 123456hanyang.ac.kr ), Serena Nik-Zainal ( snz@ 123456sanger.ac.uk ), Mike Stratton ( mrs@ 123456sanger.ac.uk ), Alain Viari ( Alain.Viari@ 123456inria.fr )

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