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      Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

      research-article
      1 , 1 , 2 , 1 , 2 , 1 , 3 , 3 , 4 , 4 , 1 , 1 , 1 , 5 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 6 , 4 , 4 , 7 , 2 , 2 , 1 , 7 , 8 , 9 , 8 , 9 , 3 , 1 , 1 , 1 , 1 , 2 , 2 , 6 , 6 , 10 , 2 , 11 , 1 , 2 , 12 , 1 , 1 , 12 , 12 , 5 , 5 , 13 , 13 , 13 , 13 , 1 , 14 , 15 , 14 , 16 , 17 , 18 , 18 , 3 , 3 , 3 , 3 , 19 , 20 , 20 , 21 , 22 , 23 , 24 , 24 , 25 , 26 , 27 , 28 , 29 , 4 , 30 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 1 , 1 , 44 , 44 , 45 , 46 , 46 , 46 , 2 , 6 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 53 , 54 , 55 , 56 , 3 , 3 , 8 , 9 , 57 , 46 , 4 , 3 , 1 , 2
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          Summary

          The early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a tumour-specific phylogenetic approach to ctDNA profiling in the first 100 TRACERx ( TRAcking non-small cell lung Cancer Evolution through therapy ( Rx)) study participants, including one patient co-recruited to the PEACE ( Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies

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          Most cited references32

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          Is Open Access

          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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            Cancer Statistics, 2017.

            Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017;67:7-30. © 2017 American Cancer Society.
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              Global cancer statistics.

              The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
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                Author and article information

                Contributors
                On behalf of : on behalf of the TRACERx and PEACE consortia
                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                20 July 2017
                26 April 2017
                14 February 2018
                : 545
                : 7655
                : 446-451
                Affiliations
                [1 ]Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT
                [2 ]Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT
                [3 ]Natera Inc., 201 Industrial Rd., San Carlos, United States, CA 94070
                [4 ]Cancer Studies, University of Leicester, Leicester, United Kingdom, LE2 7LX
                [5 ]Department of Pathology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [6 ]Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT
                [7 ]Department of Nuclear Medicine, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [8 ]Brigham and Women’s Hospital, Boston, MA 02115, USA
                [9 ]Harvard Medical School, Boston, MA 02115, USA
                [10 ]Tumour Profiling Unit Genomics Facility, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB
                [11 ]Renal and Skin Units, The Royal Marsden Hospital, London, SW3 6JJ
                [12 ]Department of Oncology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [13 ]Department of Cardiothoracic Surgery, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [14 ]Department of Respiratory Medicine, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [15 ]Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, Rayne Building. University College London, 5 University Street. London. WC1E 6JF
                [16 ]Department of Radiology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, United Kingdom, NW1 2BU
                [17 ]Institute of Cancer Studies, University of Manchester, Oxford Road, Manchester, M13 9PL
                [18 ]The Christie Hospital, Manchester, United Kingdom, M20 4BX
                [19 ]Department of Cardiothoracic Surgery, University Hospital South Manchester, Manchester, M23 9LT
                [20 ]Department of Pathology, University Hospital South Manchester, Manchester, M23 9LT
                [21 ]North West Lung Centre, University Hospital South Manchester, Manchester, United Kingdom, M23 9LT
                [22 ]Department of Thoracic Surgery, Birmingham Heartlands Hospital, Birmingham, United Kingdom, B9 5SS
                [23 ]Department of Medical Oncology, Birmingham Heartlands Hospital, Birmingham, United Kingdom, B9 5SS
                [24 ]Department of Cellular Pathology, Birmingham Heartlands Hospital, Birmingham, United Kingdom, B9 5SS
                [25 ]Department of Medical Oncology, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom, AB25 2ZN
                [26 ]Department of Cardiothoracic Surgery, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, United Kingdom, AB25 2ZD
                [27 ]Department of Pathology, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom, AB25 2ZD
                [28 ]Department of Respiratory Medicine, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, United Kingdom, AB25 2ZN
                [29 ]Department of Radiology, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom, AB25 2ZN
                [30 ]Department of Thoracic Surgery, Glenfield Hospital, Leicester, LE3 9QP
                [31 ]Department of Radiotherapy, North Middlesex University Hospital, London N18 1QX
                [32 ]Department of Respiratory Medicine, Royal Free Hospital, Pond Street, London, NW3 2QG
                [33 ]Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Wellhouse Lane, Barnet, United Kingdom, EN5 3DJ
                [34 ]Department of Respiratory Medicine, The Princess Alexandra Hospital, Hamstel Rd, Harlow CM20 1QX
                [35 ]Department of Clinical Oncology, St.Luke's Cancer Centre, Royal Surrey County Hospital, Guildford, GU2 7XX
                [36 ]Department of Pathology, Ashford and St. Peters' Hospital, Guildford Road, Chertsey, Surrey, KT16 0PZ
                [37 ]Department of Respiratory Medicine, Ashford and St. Peters' Hospital, Guildford Road, Chertsey, Surrey, KT16 0PZ
                [38 ]Department of Radiology, Ashford and St. Peters' Hospital, Guildford Road, Chertsey, Surrey, KT16 0PZ
                [39 ]Department of Clinical Oncology, Velindre Hospital, Cardiff, Wales, United Kingdom, CF14 2TL
                [40 ]Department of Cardiothoracic Surgery, University Hospital Llandough, Cardiff, Wales, United Kingdom, CF64 2XX
                [41 ]Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Heath Park Cardiff, Wales U.K
                [42 ]Department of Radiology, University Hospital Llandough, Cardiff, Wales, United Kingdom, CF64 2XX
                [43 ]Department of Respiratory Medicine, University Hospital Llandough, Cardiff, Wales, United Kingdom, CF64 2XX
                [44 ]UCL ECMC GCLP Facility, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT
                [45 ]Department of Respiratory Medicine, The Whittington Hospital NHS Trust, United Kingdom, N19 5NF
                [46 ]University College London, Cancer Research UK & UCL Cancer Trials Centre, London, United Kingdom, W1T 4TJ
                [47 ]Centre for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark
                [48 ]Computational Health Informatics Program (CHIP), Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
                [49 ]MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary
                [50 ]Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
                [51 ]Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT
                [52 ]Department of Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT
                [53 ]Cancer Immunology Unit, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT
                [54 ]Cancer Genomics Laboratory, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT
                [55 ]Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium
                [56 ]Cancer Research UK Manchester Institute, Manchester, United Kingdom, M20 4BX
                [57 ]Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, United States, MA 02215-5450
                Author notes
                Correspondence should be addressed to C.S. Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 3rd Floor South West, 1 Midland Road, London, NW1 1A, Charles.Swanton@ 123456crick.ac.uk , Office +44 203 796 2047
                [*]

                These authors contributed equally to this work

                [+]

                These authors contributed equally to this work

                Article
                EMS72313
                10.1038/nature22364
                5812436
                28445469
                7546148f-c203-4755-b5da-367d4a8c1aee

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