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

Tyler S. Alioto, Ivo Buchhalter, Sophia Derdak, Barbara Hutter, Matthew D. Eldridge, Eivind Hovig, Lawrence E. Heisler, Timothy A. Beck, Jared T. Simpson, Laurie Tonon, Anne-Sophie Sertier, Ann-Marie Patch, Natalie Jäger, Philip Ginsbach, Ruben Drews, Nagarajan Paramasivam, Rolf Kabbe, Sasithorn Chotewutmontri, Nicolle Diessl, Christopher Previti, Sabine Schmidt, Benedikt Brors, Lars Feuerbach, Michael Heinold, Susanne Gröbner, Andrey Korshunov, Patrick S. Tarpey, Adam P. Butler, Jonathan Hinton, David Jones, Andrew Menzies, Keiran Raine, Rebecca Shepherd, Lucy Stebbings, Jon W. Teague, Paolo Ribeca, Francesc Castro Giner, Sergi Beltran, Emanuele Raineri, Marc Dabad, Simon C. Heath, Marta Gut, Robert E. Denroche, Nicholas J. Harding, Takafumi N. Yamaguchi, Akihiro Fujimoto, Hidewaki Nakagawa, Víctor Quesada, Rafael Valdés-Mas, Sigve Nakken, Daniel Vodák, Lawrence Bower, Andrew G. Lynch, Charlotte L. Anderson, Nicola Waddell, John V. Pearson, Sean M. Grimmond, Myron Peto, Paul Spellman, Minghui He, Cyriac Kandoth, Semin Lee, John Zhang, Louis Létourneau, Singer Ma, Sahil Seth, David Torrents, Liu Xi, David A. Wheeler, Carlos López-Otín, Elías Campo, Peter J. Campbell, Paul C. Boutros, Xose S. Puente, Daniela S. Gerhard, Stefan M. Pfister, John D. McPherson, Thomas J. Hudson, Matthias Schlesner, Peter Lichter, Roland Eils, David T. W. Jones and Ivo G. Gut ()
Additional contact information
Tyler S. Alioto: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Ivo Buchhalter: German Cancer Research Center
Sophia Derdak: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Barbara Hutter: German Cancer Research Center
Matthew D. Eldridge: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre
Eivind Hovig: Institute for Cancer Research, Oslo University Hospital
Lawrence E. Heisler: Ontario Institute for Cancer Research
Timothy A. Beck: Ontario Institute for Cancer Research
Jared T. Simpson: Ontario Institute for Cancer Research
Laurie Tonon: Synergie Lyon Cancer Foundation, Centre Léon Bérard, Cheney C
Anne-Sophie Sertier: Synergie Lyon Cancer Foundation, Centre Léon Bérard, Cheney C
Ann-Marie Patch: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland
Natalie Jäger: German Cancer Research Center
Philip Ginsbach: German Cancer Research Center
Ruben Drews: German Cancer Research Center
Nagarajan Paramasivam: German Cancer Research Center
Rolf Kabbe: German Cancer Research Center
Sasithorn Chotewutmontri: Genome and Proteome Core Facility, German Cancer Research Center
Nicolle Diessl: Genome and Proteome Core Facility, German Cancer Research Center
Christopher Previti: Genome and Proteome Core Facility, German Cancer Research Center
Sabine Schmidt: Genome and Proteome Core Facility, German Cancer Research Center
Benedikt Brors: German Cancer Research Center
Lars Feuerbach: German Cancer Research Center
Michael Heinold: German Cancer Research Center
Susanne Gröbner: Heidelberg University Hospital
Andrey Korshunov: Heidelberg University Hospital
Patrick S. Tarpey: Wellcome Trust Sanger Institute
Adam P. Butler: Wellcome Trust Sanger Institute
Jonathan Hinton: Wellcome Trust Sanger Institute
David Jones: Wellcome Trust Sanger Institute
Andrew Menzies: Wellcome Trust Sanger Institute
Keiran Raine: Wellcome Trust Sanger Institute
Rebecca Shepherd: Wellcome Trust Sanger Institute
Lucy Stebbings: Wellcome Trust Sanger Institute
Jon W. Teague: Wellcome Trust Sanger Institute
Paolo Ribeca: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Francesc Castro Giner: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Sergi Beltran: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Emanuele Raineri: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Marc Dabad: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Simon C. Heath: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Marta Gut: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Robert E. Denroche: Ontario Institute for Cancer Research
Nicholas J. Harding: Ontario Institute for Cancer Research
Takafumi N. Yamaguchi: Ontario Institute for Cancer Research
Akihiro Fujimoto: RIKEN Center for Integrative Medical Sciences
Hidewaki Nakagawa: RIKEN Center for Integrative Medical Sciences
Víctor Quesada: Universidad de Oviedo—IUOPA, C/Fernando Bongera s/n
Rafael Valdés-Mas: Universidad de Oviedo—IUOPA, C/Fernando Bongera s/n
Sigve Nakken: Institute for Cancer Research, Oslo University Hospital
Daniel Vodák: Institute for Cancer Research, Oslo University Hospital
Lawrence Bower: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre
Andrew G. Lynch: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre
Charlotte L. Anderson: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre
Nicola Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland
John V. Pearson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland
Sean M. Grimmond: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland
Myron Peto: Knight Cancer Institute, Oregon Health and Science University
Paul Spellman: Knight Cancer Institute, Oregon Health and Science University
Minghui He: BGI-Shenzhen
Cyriac Kandoth: The Genome Institute, Washington University
Semin Lee: Harvard Medical School
John Zhang: Harvard Medical School
Louis Létourneau: McGill University
Singer Ma: Center for Biomolecular Science and Engineering, University of California
Sahil Seth: MD Anderson Cancer Center, Houston, Texas 77030, USA
David Torrents: IRB-BSC Joint Research Program on Computational Biology, Barcelona Supercomputing Center
Liu Xi: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza
David A. Wheeler: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza
Carlos López-Otín: Universidad de Oviedo—IUOPA, C/Fernando Bongera s/n
Elías Campo: Hematopathology Unit, Hospital Clinic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer
Peter J. Campbell: Wellcome Trust Sanger Institute
Paul C. Boutros: Synergie Lyon Cancer Foundation, Centre Léon Bérard, Cheney C
Xose S. Puente: Universidad de Oviedo—IUOPA, C/Fernando Bongera s/n
Daniela S. Gerhard: National Cancer Institute, Office of Cancer Genomics, 31 Center Drive, 10A07, Bethesda, Maryland 20892-2580, USA
Stefan M. Pfister: Heidelberg University Hospital
John D. McPherson: Ontario Institute for Cancer Research
Thomas J. Hudson: Ontario Institute for Cancer Research
Matthias Schlesner: German Cancer Research Center
Peter Lichter: German Cancer Research Center (DKFZ)
Roland Eils: German Cancer Research Center
David T. W. Jones: German Cancer Research Center (DKFZ)
Ivo G. Gut: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms10001

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