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From Genome to Cancer--Why the Time Is Right

When in 1986 I suggested a new project directed at identifying all human genes, one of my overriding goals was to find those genes involved in cancer development--a feat I hoped would lead to new tools for cancer research and, ultimately, to new therapies. That original human genome project has now been carried out and has demonstrated its usefulness for the discovery of genes involved in many diseases, including cancer. Moreover, the genome sequencing effort has been extended to other organisms--from bacteria to chimpanzees--and is showing the unity of life by revealing how many genes distant species share in common.

In the course of this work, new technologies have also provided a much more detailed understanding of the complicated processes by which genes give rise to a variety of functional molecules. An important outcome of this research is the realization that genes do not act alone but are participants in extensive networks of activity within cells. Any change in the functioning of one gene can therefore be accompanied by changes in the workings of multiple genes and proteins involved in the cells' self-maintenance.

The complexity of this system in normal cells is evident in what we already know about cancer--that it results from the stepwise loss of such cellular self-control, which becomes more and more complete as the disease progresses. That progression is caused only in part by physical alterations, or mutations, in specific genes; mostly it is the result of consequent changes in the activity of many other genes involved in cell regulation. Single genes may therefore be responsible in the initiation of cancer and so potential therapeutic targets. To reach the more advanced stages of these cancers (such as the acute phase of myeloid leukemia or the metastatic phase of other cancers), however, the participation of many other genes is required. Most of them are still unknown.

An exception is the recently observed phenomenon of oncogene addiction in certain tumor cells: despite the presence of numerous mutations to the cellular genome, turning off the activity of one so-called oncogene causes the cells to commit suicide via a mechanism known as apoptosis. But how generally this phenomenon occurs is also unknown. To approach these questions, it will be necessary to have a complete catalogue of the structural and functional alterations of genes and other cellular comp¿onents that cause the loss of regulation in cancer cells. This process, in turn, will require a complete determination of their connections into networks by computational means--a task for the future.

On the way to this goal, however, many other unanswered questions can be explored by the research community. A possible role for stem cells in cancer, for example, is supported by similarities in the behavior of stem cells and cancer cells: both have an unlimited ability to divide; both are very sensitive to the cellular environment, or niche, in which they grow; and many of the genes known to be active in stem cells are also activated in cancer cells.

The advent of genomics has provided welcome insight into the mechanisms by which normal cells become cancerous, but our picture is still incomplete. The time has come to obtain a truly comprehensive catalogue of the genes involved in cancer, bringing to bear all the power of the new tools of genomics and molecular biology to the problem. The Cancer Genome Atlas project aims to do just that.

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