An eye-opening article from the International Cancer Genome Consortium (ICGC) is 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 CNAG and the German Cancer Research Center 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 tumor 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% 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 centers (0.3%). 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) and leader of the Executive Committee of the ICGC, 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 context
The International Cancer Genome Consortium is an international effort to establish a comprehensive description of genomic, transcriptomic and epigenomic changes in 50 different tumor 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 tumor arising in the cerebellum). Spain’s contribution to the ICGC is on chronic lymphocytic leukemia (CLL) with a consortium led by Elías Campo and 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 tumor), 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 tumor 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.

Work of reference:
A comprehensive assessment of somatic mutation detection in cancer using whole genome sequencing.