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See Inside March 2007

Mapping the Cancer Genome

Pinpointing the genes involved in cancer will help chart a new course across the complex landscape of human malignancies

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"If we wish to learn more about cancer, we must now concentrate on the cellular genome." Nobel laureate Renato Dulbecco penned those words more than 20 years ago in one of the earliest public calls for what would become the Human Genome Project. "We are at a turning point," Dulbecco, a pioneering cancer researcher, declared in 1986 in the journal Science. Discoveries in preceding years had made clear that much of the deranged behavior of cancer cells stemmed from damage to their genes and alterations in their functioning. "We have two options," he wrote. "Either try to discover the genes important in malignancy by a piecemeal approach, or & sequence the whole genome."

Dulbecco and others in the scientific community grasped that sequencing the human genome, though a monumental achievement itself, would mark just the first step of the quest to fully understand the biology of cancer. With the complete sequence of nucleotide bases in normal human DNA in hand, scientists would then need to classify the wide array of human genes according to their function--which in turn could reveal their roles in cancer. Over the span of two decades Dulbecco's vision has moved from pipe dream to reality. Less than three years after the Human Genome Project's completion, the National Institutes of Health has officially launched the pilot stage of an effort to create a comprehensive catalogue of the genomic changes involved in cancer: The Cancer Genome Atlas (TCGA).

The main reason to pursue this next ambitious venture in large-scale biology with great urgency is cancer's terrible toll on humankind. Every day more than 1,500 Americans die from cancer--about one person every minute. As the U.S. population ages, this rate is expected to rise significantly in the years ahead unless investigators find ways to accelerate the identification of new vulnerabilities within cancerous cells and develop novel strategies for attacking those targets.

Still, however noble the intent, it takes more than a desire to ease human suffering to justify a research enterprise of this magnitude. When applied to the 50 most common types of cancer, this effort could ultimately prove to be the equivalent of more than 10,000 Human Genome Projects in terms of the sheer volume of DNA to be sequenced. The dream must therefore be matched with an ambitious but realistic assessment of the emerging scientific opportunities for waging a smarter war against cancer.

A Disease of Genes
The idea that alterations to the cellular genome lie at the heart of all forms of cancer is not new. Since the first identification in 1981 of a cancer-promoting version of a human gene, known as an oncogene, scientists have increasingly come to understand that cancer is caused primarily by mutations in specific genes. The damage can be incurred through exposure to toxins or radiation, by faulty DNA repair processes or by errors that occur when DNA is copied prior to cell division. In relatively rare cases, a cancer-predisposing mutation is carried within a gene variant inherited from one's ancestors.

Whatever their origin, these mutations disrupt biological pathways in ways that result in the uncontrolled cell replication, or growth, that is characteristic of cancer as well as other hallmarks of malignancy, such as the ability to invade neighboring tissues and to spread to sites throughout the body. Some mutations may disable genes that normally protect against abnormal cell behavior, whereas others increase the activity of disruptive genes. Most cells must acquire at least several of these alterations before they become transformed into cancer cells--a process that can take years.

Over the past two decades many individual research groups have used groundbreaking molecular biology techniques to search for mutations in genes that are likely candidates for wreaking havoc on normal patterns of cell growth and behavior. This approach has identified about 350 cancer-related genes and yielded many significant insights into this diabolical disease. A database of these changes, called the catalogue of somatic mutations in cancer, or COSMIC, is maintained by Michael Stratton's group at the Wellcome Trust Sanger Institute in Cambridge, England. But no one imagines that it is the complete list.

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