Building the foundations for Cancer Genomic Analysis for Research and Clinical Diagnostics

  • A study published in the prestigious journal Nature Communications revealed a high degree of heterogeneity in how cancer genome sequencing is done at different institutions across the globe;
  • This result lays the foundation for the coming era of cancer genomics by creating guidelines and providing new tools for achieving higher quality data, for better diagnosis and precision medicine;
  • The Centro Nacional de Analisis Genómico (CNAG-CRG) and the German Cancer Research Center (DKFZ) took leading roles in this international effort by 78 different institutions.

BARCELONA, Dec. 9, 2015 /CNW/ - An eye-opening article from the International Cancer Genome Consortium (ICGC) was published today in the prestigious journal Nature Communications. It lays a foundation for the coming era of research in cancer genomics. The project, led by the Centro Nacional de Analisis Genómico (CNAG-CRG) and the German Cancer Research Center (DKFZ) is the result of an effort to create reliable standards to obtain accurate results in the detection of somatic mutations, which are a hallmark of cancer genomes. Somatic mutations are genetic alterations spontaneously acquired by a cell that can be passed to the progeny of the mutated cell in the course of cell division and tumour growth. Somatic mutations differ from germline variants, which are inherited from parents to children.

The study, involving 83 researchers from 78 research institutions participating in the International Cancer Genomics Consortium, identified big differences in procedures and quality of cancer genome sequencing between sequencing centers. This led to dramatic discrepancies in the number and types of gene mutations detected when using the same cancer genome sequences for analysis. Out of >1,000 confirmed somatic single-base mutations in the cancer genome analyzed, only 40 per cent were unanimously identified by all participating teams. Small insertions or deletions in the DNA sequence were even more challenging - only a single somatic insertion/deletion mutation out of 337 was identified in all centres (0.3 per cent). As a consequence, the Consortium has established a reference mutation dataset to assess analytical procedures. The 'gold-set' reference database has helped the ICGC community to improve procedures for identifying more true somatic mutations in cancer genomes while making fewer false positive calls.

As whole genome sequencing of cancer genomes is increasingly being used as a clinical tool, full understanding of the variables affecting sequencing analysis output quality is required. The key points to consider and the necessary tools for improvement are provided here. "The findings of our study have far-reaching implications for cancer genome analysis. We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results," says Ivo Gut, senior author of the publication and director of the CNAG-CRG in Barcelona.

David Jones, a Senior Scientist at the DKFZ who co-led the study, commented that "as the latest technological advances in cancer genome analysis become more widely available to support personalized cancer medicine, it is vitally important that rigorous quality testing is applied to ensure accuracy and consistency of results. We hope that our study can provide a framework for this process, to help researchers in providing the best possible analysis of patients' samples."

Tom Hudson, President and Scientific Director of the Ontario Institute for Cancer Research (OICR) declared that "At the founding of the ICGC, members of the Consortium agreed that the guidelines for "best practices" could be revised as needed to adapt to new technologies and knowledge. This benchmarking exercise gives the research community gained confidence in calling and verifying somatic mutations - a step forward to improve clinical decisions based on genomic analyses."

"The promise of cancer genomics relies on accurate and robust detection of mutations affecting DNA," said Dr. Jared Simpson, Principal Investigator in OICR's Informatics and Bio-computing Program. "This paper helps us track progress on this important problem by both identifying the strengths of our current approaches and where further work is needed."

"This project really demonstrates that while new technologies can bring challenges in data quality and data analysis, when the international community comes together in a collaborative way these can rapidly become results," said Dr. Paul Boutros, Principal Investigator in OICR's Informatics and Bio-computing Program. "The results of this collaboration are going to significantly improve the quality of sequencing and data analysis we do here at OICR, for example as part of the Canadian Prostate Cancer Genome Network."

The context
The International Cancer Genome Consortium is an international effort to establish a comprehensive description of genomic, transcriptomic and epigenomic changes in 50 different tumour types and/or subtypes which are of clinical and societal importance across the globe. The ICGC is characterizing over 25,000 cancer genomes from many forms of cancer. There are 78 projects supported by different national and international funding agencies. For this project, two different types of cancer genomes were studied: chronic lymphocytic leukemia and medulloblastoma (a malignant pediatric brain tumour arising in the cerebellum). Spain's contribution to the ICGC is on chronic lymphocytic leukemia (CLL) with a consortium led by Dr. Elías Campo and Dr. Carlos López-Otín from the Hospital Clínic de Barcelona, and the University of Oviedo, respectively, with other partners including the Hospital of Salamanca, the Barcelona Supercomputing Center, the Catalan Institute of Oncology, the National Cancer Research Center and the CNAG-CRG. The genomic research on medulloblastoma and pilocytic astrocytoma (another common pediatric brain tumour), is being conducted by the "PedBrain Tumor Research Project", the first German contribution to the ICGC. In this research project, where the German Cancer Research Center (DKFZ) plays a key role, the entire tumour genome of a patient is analyzed and compared to the normal genome of the same patient to decipher the molecular causes for these types of cancer. The PedBrain Tumor Research Project started in early 2010 and is a collaborative effort between the DKFZ, the NCT, Heidelberg University, the University Clinics in Heidelberg and Düsseldorf, the EMBL and the Max-Planck Institute for Molecular Genetics.

The Centro Nacional de Analisis Genómico (CNAG-CRG) was created on 2009 as a centre of reference for genomics and a key part of the scientific infrastructure required to advance biomedical and genomics research in Catalonia and Spain. Its mission is to carry out genome projects aimed at improving the health and quality of life for people, in collaboration with national and international scientists, to promote Spanish genomics and to ensure its competitiveness in the areas of biomedicine and biology as well as the agrofood sector. With its legal incorporation into the Centre for Genomic Regulation (CRG) on July 1, 2015, these two centres have joined forces to go even further in genome research.

The German Cancer Research Center
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety per cent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

The Ontario Institute for Cancer Research
OICR hosts the ICGC's Secretariat and Dr. Tom Hudson, OICR's President and Scientific Director, chairs both its Executive Committee and its International Scientific Steering Committee. The data produced by the ICGC project teams are housed on the ICGC website at and the Data Coordination Centre is based at OICR. More than 14,000 cancer genomes are currently in the ICGC database and are made rapidly available to qualified investigators around the world. As of December 2015, there are commitments from funding organizations in Asia, Australia, Europe, North America and South America for 89 project teams in 17 jurisdictions to study more than 25,000 tumour genomes. OICR has two projects, one on pancreatic cancer and one being conducted on prostate cancer in partnership with Prostate Cancer Canada.

Reference work:
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, Ivo G. Gut.(2015). A comprehensive assessment of somatic mutation detection in cancer using whole genome sequencing. Nature Communications.

Participant centers:
Centro Nacional de Analísis Genómico (CNAG-CRG, Barcelona, Spain), German Cancer Research Center (DKFZ, Heidelberg, Germany), Cancer Research UK Cambridge Institute (UK), Norwegian Cancer Genomics Consortium (Oslo, Norway), Oslo University Hospital (Norway), University of Oslo (Norway), Ontario Institute for Cancer Research (Canada), Synergie Lyon Cancer Foundation (France), Queensland Centre for Medical Genomics (Australia), QIMR Berghofer Medical Research Institute (Australia), Stanford University (USA), Heidelberg University Hospital (Germany), Wellcome Trust Sanger Institute (Cambridge, UK), RIKEN Center for Integrative Medical Sciences (Tokyo, Japan), Universidad de Oviedo (Spain), The University of Melbourne (Australia), Wolfson Cancer Research Centre (Glasgow, Scotland), Knight Cancer Institute (Portland, USA), BGI-Schenzhen (China), The Genome Institute (St. Louis, USA), Harvard Medical School (Boston, USA), MD Anderson Cancer Center (Houston, USA), McGill University (Quebec, Canada), Institut de Recerca Biomèdica (IRB, Barcelona, Spain) & Barcelona Supercomputing Center (BSC-CNS, Spain), Human Genome Sequencing Center, Hospital Clínic (UB, Barcelona, Spain) & Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS, Barcelona, Spain), University of Toronto (Canada), National Cancer Institute (Bethesda, USA).

SOURCE Ontario Institute for Cancer Research

For further information: Centro Nacional de Análisis Genómico (CNAG-CRG), Dr. Ivo G. Gut, Director of the CNAG-CRG, +34 934020580,

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