Guest Update by Dr. Anna Barker
Mapping the Cancer Genome
The following captures some of the highlights from an article in the March 2007 Scientific American magazine that I wrote with National Human Genome Research Institute (NHGRI) Director Dr. Francis Collins. It represents one of the first detailed discussions of The Cancer Genome Atlas in a publication that is widely read by a variety of audiences.
Writing in Science in 1986, Dr. Renato Dulbecco, a pioneering cancer researcher and Nobel Laureate declared, "We are at a turning point." 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."Over the span of 2 decades, Dr. Dulbecco's vision has moved from pipe dream to reality. Less than 3 years after the Human Genome Project's (HGP's) completion, NIH has launched the pilot stage of an effort to create a comprehensive catalog of the genomic changes involved in cancer: The Cancer Genome Atlas (TCGA).
HGP laid a solid foundation for TCGA by creating a standardized reference sequence of the 3 billion DNA base pairs in the genome of normal human tissues. Now TCGA - a pilot project focused on three cancers - will characterize a number of genomic alterations as well as the DNA sequences of specific genes and regions of DNA from tumor tissues and compare them with normal cells to identify the major genetic changes that drive the cancer development process.
Several recent developments have provided proofs of concept that identifying specific genetic changes in cancer cells can point us toward improved methods of diagnosis, treatment, and prevention.
For example, in 2001 the Wellcome Trust Sanger Institute began to use genomic sequencing technologies to explore cancer. A year later, the group found that a gene called B-RAF was mutated in about 70 percent of the malignant melanoma cases they examined. A variety of researchers set their sights on this potential new therapeutic target, and 5 years later, the most promising of these therapies are being tested in clinical trials. Other research groups have zeroed in on genetic mutations linked to certain types of breast cancer, colon cancer, leukemia, and other cancers to develop new therapies and high-value molecular diagnostics that will point physicians to those chemotherapeutic agents to which a specific patient is most likely to respond.
A strategy used at the beginning of HGP was to test protocols and technology before scaling up to full DNA sequence "production." Similarly, TCGA is beginning with a pilot project to develop and test the scientific framework that will be needed if we are to ultimately map all the genomic abnormalities involved in cancer. Over the next 3 years, NCI and NHGRI will devote $100 million to compiling an atlas of genomic changes in glioblastoma, lung cancer, and ovarian cancer.
These cancers were chosen for several reasons, including their value in gauging the feasibility of expanding this project to a much larger number of cancer types. Only if this pilot phase achieves its goals will we move forward with a full-fledged project to develop a complete cancer "atlas."
As detailed in the article, the road ahead is fraught with scientific, technological, and policy challenges - some of which are known and others as yet unknown. Among the uncertainties to be resolved: Will new sequencing technologies deliver on their early promise in time to make this effort economically feasible? How quickly can we improve and expand our toolbox for systematically detecting epigenetic changes and other large-scale genomic alterations involved in cancer, especially those associated with metastasis? How can we harness the power of computational biology to create algorithms and data portals that will prove useful to basic biologists, clinical researchers and, eventually, health care professionals on the front lines? The list goes on.
In Scientific American, Dr. Collins and I compared our position with TCGA to that of the 19th-century explorers Lewis and Clark, as they ventured up the Missouri River into the largely uncharted Northwest Territory. Although they did not find the water route across the continent, their detailed maps proved valuable to a fledgling nation in ways that President Thomas Jefferson, who dispatched the explorers, could never have imagined.
For the sake of all those whose lives have and will be touched by cancer, we can only hope our 21st century expedition into cancer biology exceeds even Renato Dulbecco's grandest dreams.