Researchers Discover Key Mutation in Acute Myeloid Leukemia
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Researchers have discovered mutations in a particular gene that affects the treatment prognosis for some patients with acute myeloid leukemia (AML), an aggressive blood cancer that kills 9,000 Americans annually. The scientists report their results in the Nov. 11, 2010, online issue of The New England Journal of Medicine.
The Washington University School of Medicine in St. Louis team initially discovered a mutation by completely sequencing the genome of a single AML patient. They then used targeted DNA sequencing on nearly 300 additional AML patient samples to confirm that mutations discovered in one gene correlated with the disease.
Although genetic changes previously were found in AML, this work shows that newly discovered mutations in a single gene, called DNA methyltransferase 3A or DNMT3A, appear responsible for treatment failure in a significant number of AML patients. The finding should prove rapidly useful in treating patients and which may provide a molecular target against which to develop new drugs.
"This is a wonderful example of the ability of the unbiased application of whole-genome, DNA sequencing to discover a frequently mutated gene in cancer that was previously unknown to be correlated with prognosis," said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, which co-funded this study. "This may quickly lead to a change in medical care because physicians may now screen for these mutations in patients and adjust their treatment accordingly."
The study was carried out by researchers from the Washington University Genome Center and the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. In the study, the researchers found DNMT3A mutations in 21 percent of all AML patients studied and in 34 percent of the patients classified as having an intermediate risk of treatment failure based on widely used laboratory tests of their leukemia cells. More than half of AML patients are classified as having an intermediate risk and are then typically treated with standard chemotherapy.
For patients with the DNMT3A mutation, however, chemotherapy may not be the best first treatment. "We have not had a reliable way to predict which of these patients will respond to the standard treatment," said lead author and hematologist Timothy Ley, M.D., the Lewis T. and Rosalind B. Apple Professor of Medicine at Washington University School of Medicine. "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."
Patients with the mutation survived for a median of just over a year, compared to the median survival of nearly 3.5 years among those without the mutation. "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, Ph.D., director of Washington University's Genome Center.
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 Washington University investigators caution that the sample size was small and follow-up studies will be needed to confirm these initial findings.
"This discovery is a clear example of the power of comprehensive analysis of cancer genomes," said Francis S. Collins, M.D., Ph.D., 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 Washington University School of Medicine in St. Louis team initially discovered a mutation by completely sequencing the genome of a single AML patient. They then used targeted DNA sequencing on nearly 300 additional AML patient samples to confirm that mutations discovered in one gene correlated with the disease.
Although genetic changes previously were found in AML, this work shows that newly discovered mutations in a single gene, called DNA methyltransferase 3A or DNMT3A, appear responsible for treatment failure in a significant number of AML patients. The finding should prove rapidly useful in treating patients and which may provide a molecular target against which to develop new drugs.
"This is a wonderful example of the ability of the unbiased application of whole-genome, DNA sequencing to discover a frequently mutated gene in cancer that was previously unknown to be correlated with prognosis," said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, which co-funded this study. "This may quickly lead to a change in medical care because physicians may now screen for these mutations in patients and adjust their treatment accordingly."
The study was carried out by researchers from the Washington University Genome Center and the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. In the study, the researchers found DNMT3A mutations in 21 percent of all AML patients studied and in 34 percent of the patients classified as having an intermediate risk of treatment failure based on widely used laboratory tests of their leukemia cells. More than half of AML patients are classified as having an intermediate risk and are then typically treated with standard chemotherapy.
For patients with the DNMT3A mutation, however, chemotherapy may not be the best first treatment. "We have not had a reliable way to predict which of these patients will respond to the standard treatment," said lead author and hematologist Timothy Ley, M.D., the Lewis T. and Rosalind B. Apple Professor of Medicine at Washington University School of Medicine. "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."
Patients with the mutation survived for a median of just over a year, compared to the median survival of nearly 3.5 years among those without the mutation. "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, Ph.D., director of Washington University's Genome Center.
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 Washington University investigators caution that the sample size was small and follow-up studies will be needed to confirm these initial findings.
"This discovery is a clear example of the power of comprehensive analysis of cancer genomes," said Francis S. Collins, M.D., Ph.D., 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."
