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Nat Commun. 2015 Dec 9;6:10001. doi: 10.1038/ncomms10001.

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

Author information

  • 1CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain.
  • 2Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
  • 3Division of Theoretical Bioinformatics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • 4Division of Applied Bioinformatics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • 5Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
  • 6Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
  • 7Department of Informatics, University of Oslo, 0373 Oslo, Norway.
  • 8Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, Ontario, Canada M5G 0A3.
  • 9Synergie Lyon Cancer Foundation, Centre Léon Bérard, Cheney C, 28 rue Laennec, Lyon 69373, France.
  • 10Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
  • 11QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
  • 12Department of Genetics, Stanford University, Mail Stop-5120, Stanford, California 94305-5120, USA.
  • 13Genome and Proteome Core Facility, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120 Germany.
  • 14Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany.
  • 15Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, Heidelberg 69120, Germany.
  • 16Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • 17RIKEN Center for Integrative Medical Sciences, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
  • 18Universidad de Oviedo-IUOPA, C/Fernando Bongera s/n, 33006 Oviedo, Spain.
  • 19The Bioinformatics Core Facility, Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0310 Oslo, Norway.
  • 20Victorian Life Sciences Computation Initiative, The University of Melbourne, Melbourne, Victoria 3053, Australia.
  • 21WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland G61 1QH, UK.
  • 22Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
  • 23BGI-Shenzhen, Shenzhen 518083, China.
  • 24The Genome Institute, Washington University, St Louis, Missouri 63108, USA.
  • 25Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 26MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • 27McGill University, Montreal, Quebec, Canada QC H3A 0G4.
  • 28Center for Biomolecular Science and Engineering, University of California, Santa Cruz, California 95064, USA.
  • 29IRB-BSC Joint Research Program on Computational Biology, Barcelona Supercomputing Center, 08034 Barcelona, Spain.
  • 30Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
  • 31Hematopathology Unit, Department of Pathology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
  • 32Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
  • 33National Cancer Institute, Office of Cancer Genomics, 31 Center Drive, 10A07, Bethesda, Maryland 20892-2580, USA.
  • 34Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • 35Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
  • 36Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120,Germany.
  • 37Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 38Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg 69120, Germany.
  • 39Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg 69120, Germany.


As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

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