Nov. 11, 2010 Decoding the DNA of a woman who died of acute myeloid leukemia (AML) has led researchers at Washington University School of Medicine in St. Louis to a gene that they found to be commonly altered in many patients who died quickly of the disease.
The findings, if confirmed in larger studies, suggest that a diagnostic test for mutations in the gene could identify AML patients who need more aggressive treatment right from the start. The new discovery also provides a concrete target for developing improved therapies against AML, a fast-moving blood cancer that kills 9,000 Americans annually.
Studying nearly 300 AML patients, the researchers found those with a mutation in the DNA methyltransferase 3A gene, or DNMT3A, survived for a median of just over one year after their diagnosis, compared with nearly 3.5 years for those without a mutation. The research is published online Nov. 10 in the New England Journal of Medicine.
Notably, the investigators found the mutations in one-third of the patients whose prognosis would be unclear, based on current diagnostic tests. These patients typically receive standard chemotherapy drugs as a first-line treatment.
"Based on what we found, if a patient has a DNMT3A mutation, it looks like you're going to want to treat very aggressively, perhaps go straight to bone marrow transplantation or a more intensive chemotherapy regimen," says senior author Richard K. Wilson, PhD, director of Washington University's Genome Center and professor of genetics and of molecular microbiology.
The study was conducted by a large team of scientists at The Genome Center and the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. They are pioneers in using a comprehensive, genome-wide approach to unravel the genetic basis of cancer. By decoding the genome -- all the DNA -- of cancer patients and their tumor cells, they can find critical mutations at the root of the disease. Then, the researchers can look for those errors in other patients.
The new research dovetails with the work that Washington University genome scientists are engaged in as part of The Cancer Genome Atlas, a joint project of the National Cancer Institute and National Human Genome Research Institute to unravel the genetic basis of more than 20 different types of cancer.
"This discovery is a clear example of the power of comprehensive analysis of cancer genomes," says Francis Collins, MD, PhD, director of the National Institutes of Health. "By using high-throughput DNA sequencing, researchers will be able to discover all of the common genetic changes that contribute to cancer. With that knowledge, a growing list of targeted treatments will be developed, based on a firm biological understanding of the disease."
The researchers zeroed in on the DNMT3A mutation by decoding the genome of a woman who died of AML in her 50s and comparing it to the genome of her cancer cells. Then they looked to see if the DNMT3A gene was altered in leukemia cells from 281 other patients with AML. They found mutations in 62 of them, or 21 percent.
Most notably, however, they found DNMT3A mutations in 34 percent (56 of 166) of patients who had been classified as "intermediate risk," based on an analysis of chromosomes in their leukemia cells. Doctors routinely look at these chromosomes to determine the extent to which they have broken apart and rearranged themselves, an indicator of the severity of the disease.
More than half of AML patients have this intermediate-risk profile. Their chromosomes look normal or have very minor changes. While some do well on standard chemotherapy, many others do poorly. And therein lies the problem.
"We have not had a reliable way to predict which of these patients will respond to the standard treatment," says lead author and hematologist Timothy Ley, MD, the Lewis T. and Rosalind B. Apple Professor of Medicine and professor of genetics. "In the cases we studied, mutations in the DNMT3A gene trump everything else we've found so far to predict adverse outcomes in intermediate-risk AML."
As part of the new research, the investigators looked to see which treatments the patients received and how they fared. Those with DNMT3A mutations treated with bone marrow transplants lived longer than those who received only chemotherapy, but the investigators caution that the sample size was small. They say follow-up studies are needed to confirm the benefit of bone marrow transplants in these patients.
Patients over age 60 fared particularly poorly if they had a DNMT3A mutation. Of the 17 in the study, none lived longer than 18 months.
The researchers did not find any DNMT3A mutations in the 79 patients whose chromosomes indicated they had a "favorable risk." Those patients would be expected to respond well to standard treatments.
AML is an aggressive cancer of blood-forming cells in the bone marrow. Like most cancers, it arises from mutations that accumulate in people's DNA over the course of many years and not from inherited genetic errors present at birth.
About 13,000 AML cases are expected to be diagnosed in the United States. The disease occurs most often in adults and becomes more difficult to treat as patients age. The five-year survival rate for adults with AML is about 20 percent.
The DNMT3A gene is important during fetal development and is active in blood-forming cells throughout a person's life. The Washington University researchers don't yet know how mutations in the gene are involved in the development of AML, but this is a key question they are now trying to answer.
"DNMT3A mutations appear to be relevant for how the disease develops or progresses because these mutations have such huge a impact on outcome," Ley explains.
In the patients they studied, the researchers found 34 different mutations in DNMT3A, scattered throughout the gene, which change the function of the gene in different ways. Regardless of the specific type of mutation or its location in the gene, all were linked to poor survival.
The researchers identified the first DNMT3A mutation when they sequenced the genome of leukemia cells obtained from a woman in her 50s after her AML recurred following standard treatment. In 2008, the team reported in Nature that they had sequenced the patient's own DNA and the DNA from a sample of leukemia cells taken at the time of her diagnosis. They had not found the DNMT3A mutation then because DNA sequencing technology was not as sensitive and sophisticated as it is today.
Over the next several months, the researchers anticipate many research groups will check their own banked samples of AML patients' cells for DNMT3A mutations. If their data validates the Washington University study, a diagnostic test could be developed quickly to identify patients with the mutations.
"This work represents the culmination of years of collaborative research that has focused on cataloging the mutations involved in AML," says co-author John DiPersio, MD, PhD, the Virginia E. and Sam J. Goldman Professor of Medicine, chief of the Division of Oncology and deputy director of the Siteman Cancer Center. "This research provides a pathway and a foundation for doing the same in all other malignancies, which could potentially lead to better diagnostic tests and more effective, targeted therapies."
The research was funded by the National Human Genome Research Institute, the National Cancer Institute, the National Center for Research Resources, all part of the National Institutes of Health, as well as the Barnes-Jewish Hospital Foundation and Washington University.
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- Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O'Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervel P, Tomasson MH Link DC, Graubert TA, Dipersio JF, Mardis ER, Wilson RK. DNMT3A Mutations in Acute Myeloid Leukemia. New England Journal of Medicine, 2010; DOI: 10.1056/NEJMoa1005143
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