The genomes of all cancers accumulate somatic mutations1
. These include nucleotide substitutions, small insertions and deletions, chromosomal rearrangements and copy number changes that can affect protein-coding or regulatory components of genes. In addition, cancer genomes usually acquire somatic epigenetic “marks” compared to non-neoplastic tissues from the same organ, notably changes in the methylation status of cytosines at CpG dinucleotides.
A subset of the somatic mutations in cancer cells confers oncogenic properties such as growth advantage, tissue invasion and metastasis, angiogenesis, and evasion of apoptosis2
. These are termed “driver” mutations. The identification of driver mutations will provide insights into cancer biology and highlight novel drug targets and diagnostic tests. Knowledge of cancer mutations has already led to the development of specific therapies, such as trastuzumab for HER2/neu positive breast cancers3
and imatinib, which targets BCR-ABL tyrosine kinase for the treatment of chronic myeloid leukemia4,5
. The remaining somatic mutations in cancer genomes that do not contribute to cancer development are called “passengers”. These mutations provide insights into the DNA damage and repair processes that have been operative during cancer development, including exogenous environmental exposures6,7
. In most cancer genomes, it is anticipated that passenger mutations, as well as germline variants not yet catalogued in polymorphism databases, will substantially outnumber drivers.
Large-scale analyses of genes in tumors have revealed that the mutation load in cancer is abundant and heterogeneous8-13
. Preliminary surveys of cancer genomes have already demonstrated their relevance in identifying new cancer genes that constitute potential therapeutic targets for several types of cancer, including PIK3CA14
, and histone methyltransferases and demethylases16,17
. These projects have also yielded correlations between cancer mutations and prognosis, such as IDH1 and IDH2 mutations in several types of gliomas13,18
. Advances in massively parallel sequencing technology have enabled sequencing of entire cancer genomes 19-22
Following the launch of comprehensive cancer genome projects in the United Kingdom (Cancer Genome Project)23
and the United States (The Cancer Genome Atlas)24
, cancer genome scientists and funding agencies met in Toronto (Canada) in October 2007 to discuss the opportunity to launch an international consortium. Key reasons for its formation were: (1) the scope is huge; (2) independent cancer genome initiatives could lead to duplication of effort or incomplete studies; (3) lack of standardization across studies could diminish the opportunities to merge and compare datasets; (4) the spectrum of many cancers is known to vary across the world; (5) an international consortium will accelerate the dissemination of datasets and analytical methods into the user community.
Working groups were created to develop strategies and policies that would form the basis for participation in the ICGC. The goals of the Consortium (Box 1
) were released in April 2008 (http://www.icgc.org/files/ICGC_April_29_2008.pdf
). Since then, working groups and initial member projects have further refined the policies and plans for international collaboration.
Box 1. Goals of the ICGC
- Coordinate the generation of comprehensive catalogues of genomic abnormalities (somatic mutations) in tumors in 50 different cancer types and/or subtypes which are of clinical and societal importance across the globe.
- Ensure high quality by defining the catalogue for each tumor type or subtype to include the full range of somatic mutations such as single-nucleotide variants, insertions, deletions, copy number changes, translocations and other chromosomal rearrangements, and to have the following features:
- Comprehensiveness, such that most cancer genes with somatic abnormalities occurring at a frequency of greater than 3% are discovered;
- High resolution, ideally at a single nucleotide level;
- High quality, using common standards for pathology and technology;
- Data from matched non-tumor tissue, to distinguish somatic from inherited sequence variants and aberrations;
- Generate complementary catalogues of transcriptomic and epigenomic datasets from the same tumors.
- Make the data available to the entire research community as rapidly as possible, and with minimal restrictions, to accelerate research into the causes and control of cancer.
- Coordinate research efforts so that the interests and priorities of individual participants, self-organizing consortia, funding agencies and nations are addressed, including use of the burden of disease and the minimization of unnecessary redundancy in tumor analysis efforts.
- Support the dissemination of knowledge and standards related to new technologies, software, and methods to facilitate data integration and sharing with cancer researchers around the globe.