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Building foundations for cancer genomic analysis for research, clinical diagnostics

December 9, 2015
Ontario Institute for Cancer Research
A high degree of heterogeneity has been revealed 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.

An eye-opening article from the International Cancer Genome Consortium (ICGC) was published in the 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 centres. 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."

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Journal Reference:

  1. 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. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing. Nature Communications, 2015; 6: 10001 DOI: 10.1038/NCOMMS10001

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Ontario Institute for Cancer Research. "Building foundations for cancer genomic analysis for research, clinical diagnostics." ScienceDaily. ScienceDaily, 9 December 2015. <>.
Ontario Institute for Cancer Research. (2015, December 9). Building foundations for cancer genomic analysis for research, clinical diagnostics. ScienceDaily. Retrieved May 23, 2017 from
Ontario Institute for Cancer Research. "Building foundations for cancer genomic analysis for research, clinical diagnostics." ScienceDaily. (accessed May 23, 2017).