Cancer incidence and deaths are rising worldwide as a result of the growth and aging of the human population. It is estimated that in 2007 over 12 million new cases were diagnosed across the planet and approximately 7.6 million cancer deaths occurred; these numbers will rise to an expected 27 million new cases and 17.5 million cancer deaths in 20501 if our ability to prevent, diagnose and treat cancer does not improve. The consequences of cancer for individuals, their families and society are enormous. Although it is difficult to estimate the financial costs, these are also large, through direct costs to health care systems and indirect costs of lost economic output. There are many etiological factors in cancer including infection, exposure to chemicals (e.g., in tobacco smoke), diet, radiation (e.g., in sunlight), and heredity. While several of these factors are preventable, many are not.
All cancers arise due to alterations in DNA. Some cancer-causing mutations may be present in the germline, are therefore heritable and confer an elevated risk of developing cancer. Many, however, occur over the course of a person’s lifetime in individual cells of the body and are known as somatic mutations.
Within each cancer genome, a subset of the somatic alterations are “driver” mutations in “cancer genes” which cause the cancer to develop. The search for cancer genes and the “driver” mutations within them has been a central aim of cancer research for 30 years and more than 300 genes have already been identified in which somatic alterations are associated with cancer. The study of these “cancer genes” has generated most of our biological insights into the process of oncogenesis. Cancer genes and the pathways in which they are involved have been used successfully as the targets for the development of new therapeutic agents.
Cancer genomes also carry “passenger” mutations, which do not contribute to the neoplastic phenotype and are not associated with selective growth advantage. They can, however, constitute a molecular record of each cancer’s evolutionary past, reflecting past mutagenic exposures and intrinsic defects of DNA repair. As a result, they can inform powerfully on the etiology of individual cancers.
There exist major differences among cancer types both in the cancer genes, i.e., driver mutations, that are operative and in the numbers and types of passenger mutations found. The current evidence indicates that our understanding of patterns of somatic passenger mutation in cancer is at an early stage and that there are many cancer genes still to be identified. Establishing a complete catalogue of somatic genetic changes in individual cancers will therefore reveal the full set of driver mutations and cancer genes that are operative in each type of cancer. It will also reveal the full set of passenger mutations and hence yield insights into underlying mutational processes, including exposures and DNA repair defects.
The underlying biological diversity of human cancer , even those within the same pathological class, and the multiplicity of biological pathways that may be subverted mean that individual cancers may need different treatments depending on the specific genetic abnormalities within them. Recent additions to the therapeutic arsenal used to treat cancer reflect this trend. These include therapeutic monoclonal antibodies for breast cancer with amplification of HER2/NEU, and small molecule inhibitors for chronic myeloid leukaemia carrying a BCR/ABL translocation or for lung cancer with EGFR mutations. Understanding of and attention to the underlying genetic diversity in cancer is, therefore, likely to increase the success of new cancer modalities in the future.
The sequencing of the human genome allowed the identification of the full set of protein coding and other classes of gene. Although this has catapulted the scientific community into a new era of disease research, the systematic, genome-wide identification of all somatic abnormalities in large numbers of individual cancers has not been technically feasible until recently. It is now possible to contemplate the complete cataloguing of genetic alterations in different types of cancers, with the expectation that our current ability to classify tumors will be refined and improved by classification according to the mutational profiles of each tumor. Combined with the development of rational therapies on the basis of new understanding of the genomics of the individual cancers, many new therapeutic opportunities will become available.
Creating a catalogue of mutations in cancer is an ambitious project. The International Cancer Genome Consortium (ICGC) has been organized as an international effort to harmonize the large number of projects that are now, or shortly will be, underway that have the common aim of elucidating comprehensively the genomic changes present in many forms of cancers that contribute to the burden of disease in people throughout the world. The expectations are that the outcome of the research carried out by the members of the ICGC will be extensive. First and foremost will be compendiums, available to the world-wide research community, of genomic alterations in many cancer subtypes. Second, valuable information on the methods utilized by ICGC members to produce, analyze, and integrate large genomic datasets related to cancer will be made immediately available. Third, it will be possible to compare molecular differences in specific cancer subtypes found in different geographic areas. The ICGC will facilitate communication among the members and provide a forum for coordination, with the objective of maximizing efficiency among the scientists working to understand, treat, and prevent these diseases.
1Garcia et al, Global Cancer Facts & Figures 2007, Atlanta, GA, American Cancer Society 2007.