Planting the Seeds of Prevention - Siteman Cancer Center

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Timothy Ley, MD, led the effort to unravel the first complete DNA sequence of a cancer patient. Groundbreaking Discovery Scientists Sequence First Cancer Genome 14 The Alvin J. Siteman Cancer Center Cancer is personal. Every patient’s disease is fundamentally different, and there are hundreds, perhaps thousands, of types. That’s why searching for individual culprit genes has been only partially successful. It’s also why the evolving discipline of cancer genomics — which examines the sum total of a patient’s genetic material, or genome, for functionally important changes — holds real promise for finally unraveling cancer’s genetic roots. “All of us are born with approximately 25,000 genes. A small number of mutations among them can cause cancer,” says Richard Wilson, PhD, director of Washington University School of Medicine’s Genome Center and a member of the Siteman Cancer Center senior leadership team. “A genomewide understanding of cancer, which is now possible with faster, less expensive DNA sequencing technology, is the foundation for developing more effective ways to prevent, diagnose and treat the disease.” Wilson says the Human Genome Project, an international effort to map all human genes, completed in large part at the Genome Center, gave us a huge reference book — the equivalent of the haystack. Cancer genomics is the search of that encyclopedia for relevant mutations — the needles. Until recently, no one had gone so far as to do a full side-by-side comparison of all genes from normal cells and tumor cells of the same patient.
Then late last year, a group of Washington University clinical specialists and geneticists, with the help of a brave patient and visionary philanthropist, reported the first successful effort to decode the complete DNA sequence of a cancer patient. They traced her disease — acute myelogenous leukemia (AML) — to its genetic roots. The patient, a woman in her 50s who ultimately died of her disease, contributed normal skin cells and leukemia cells from bone marrow. Comparing the two genomes, the team discovered just 10 mutations in genes that appeared to be relevant. Eight of them occurred in genes not previously linked to AML, though “they make sense,” says lead author Timothy Ley, MD, the Alan A. and Edith L. Wolff Professor of Medicine at Washington University. Francis Collins, MD, PhD, former director of the National Human Genome Research Institute, says, “In the past, cancer researchers have been ‘looking under the lamppost’ to find the causes of malignancy, but now the team from Washington University has lit up the whole street. This achievement ushers in a new era of comprehensive understanding of the fundamental nature of cancer.” Sequencing the two genomes took six months; analysis required another three. “There was no book for how to do this,” Ley says. But with that early experience in hand, a second patient’s genomic analysis required only a few months. The increase in speed makes data-intensive, genomewide evaluations possible. Wilson says sequencing techniques are 100 times faster and 100 times cheaper than they were just two years ago. The trend is important because Ley believes a complete understanding of a patient’s cancer may always require genome sequencing. As evidence, he says the team surveyed 187 additional AML patients and found none of the eight new mutations. That is neither surprising nor demoralizing to Ley. “Cancer is an extremely heterogeneous disease,” he says. “That’s why we need to devise precise therapies based on the mutations in individual cancers.” Wilson hopes that once a critical mass of data is obtained, patterns among genes will make it possible to identify cancer subtypes and design specific treatments. The cost of a complete genome sequencing study currently approaches $250,000. The groundbreaking work to sequence the first cancer genome cost more than $1 million, and the project was completed only because Alvin Siteman, for whom the Siteman Cancer Center is named, supported the effort. “Funding was and is the ultimate limiting factor,” Ley says. “We simply could not have done this without his gift.” Support also was provided by the Barnes-Jewish Hospital Foundation. Genome Center director Richard Wilson, PhD, believes cancer genomics is the key to developing better, more targeted treatments. Monetary considerations aside, genomic studies of cancer will remain challenging. Brave patients willing to reveal their genetic identities have to step forward, and it will take years to bank the necessary tissue samples. No matter the hurdles, the handbook is being written at the Genome Center and Siteman, and work to reveal the molecular basis of cancer continues for one fundamental reason. “This is not an intellectual exercise,” Ley says. “We do this for our patients.” www.siteman.wustl.edu 15
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Planting the Seeds of Prevention - Siteman Cancer Center

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