ST. LOUIS—In part by completely sequencing the genome of a single patient with acute myeloid leukemia (AML), a team of researchers the Washington University in St. Louis School of Medicine have discovered mutations in a particular gene that affects the treatment prognosis for a significant number of people with AML—an aggressive blood cancer that kills 9,000 Americans annually. In addition to perhaps improving patient treatment with existing therapeutic options, this may provide a solid molecular target for the development of new drugs to address AML.
Reporting their results in the Nov. 11, 2010, online issue of The New England Journal of Medicine, the scientists followed up the complete genome sequencing of the single patient with targeted DNA sequencing of nearly 300 additional AML patient samples to confirm that mutations discovered in one gene correlated with the disease.
It isn't the first time that researchers have identified genetic changes associated with AML, but this work shows that newly discovered mutations in a single gene, called DNA methyltransferase 3A or DNMT3A, appear to be responsible for treatment failure in a significant number of AML patients.
"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," says Dr. Eric D. Green, the director of the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, which co-funded the 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."
"This discovery is a clear example of the power of comprehensive analysis of cancer genomes," adds NIH Director Dr. Francis S. Collins. "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 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," notes Dr. Timothy Ley, lead author a hematologist and 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 Dr. Richard K. Wilson, 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; however, the Washington University investigators caution that the sample size was small and follow-up studies will be needed to confirm these initial findings.
The NIH and NHGRI are pointing to this study as a good example of what can be accomplished as part of strategies coming out of The Cancer Genome Atlas (TCGA), a partnership launched in 2006 between the National Cancer Institute and the NHGRI, which are both components of the NIH. They explain that TCGA has developed a comprehensive strategy for comparing the genome of cancer cells to the genome of normal cells from the same patient. This allows the identification of genetic changes that cause the uncontrolled growth of a cancer cell. TCGA also biologically characterizes the tumors in several other ways. Together, the TCGA data can be linked to clinical data to help researchers understand the characteristics of the tumor being studied. The project plans to analyze up to 500 patient samples of tumors and normal tissues in 20 major types of cancer over the next five years.
"Cancer is a genetic disease," says NCI Director Dr. Harold Varmus. "Every discovery teaches us more and more about the many ways genes can be deranged in a tumor cell to make it grow out of control. While we generally describe some 200 types of cancer based on where they originate in the body, genetics may show us that there are thousands of different types, each requiring different treatments. Fortunately, we are now acquiring the tools we need to understand them and to make important progress."
Washington University is a TCGA participant and has pioneered the use of comprehensive, genome-wide approaches to study cancer. Although the AML study just reported was not part of TCGA, the Washington University team has donated nearly 200 AML samples for comprehensive genomic analysis to the TCGA program.
"This work represents the culmination of years of collaborative research that has focused on cataloging the mutations involved in AML," says study co-author Dr. John Dipersio, chief of the division of oncology and deputy director of the Siteman Cancer Center. "This work provides a pathway and a foundation for doing the same in all other malignancies that could potentially lead to more effective, targeted therapies."
The AML study was supported by funding from several NIH centers and institutes, including NHGRI, NCI and the National Center for Research Resources, as well as the Barnes-Jewish Hospital Foundation and Washington University.
Reporting their results in the Nov. 11, 2010, online issue of The New England Journal of Medicine, the scientists followed up the complete genome sequencing of the single patient with targeted DNA sequencing of nearly 300 additional AML patient samples to confirm that mutations discovered in one gene correlated with the disease.
It isn't the first time that researchers have identified genetic changes associated with AML, but this work shows that newly discovered mutations in a single gene, called DNA methyltransferase 3A or DNMT3A, appear to be responsible for treatment failure in a significant number of AML patients.
"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," says Dr. Eric D. Green, the director of the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, which co-funded the 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."
"This discovery is a clear example of the power of comprehensive analysis of cancer genomes," adds NIH Director Dr. Francis S. Collins. "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 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," notes Dr. Timothy Ley, lead author a hematologist and 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 Dr. Richard K. Wilson, 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; however, the Washington University investigators caution that the sample size was small and follow-up studies will be needed to confirm these initial findings.
The NIH and NHGRI are pointing to this study as a good example of what can be accomplished as part of strategies coming out of The Cancer Genome Atlas (TCGA), a partnership launched in 2006 between the National Cancer Institute and the NHGRI, which are both components of the NIH. They explain that TCGA has developed a comprehensive strategy for comparing the genome of cancer cells to the genome of normal cells from the same patient. This allows the identification of genetic changes that cause the uncontrolled growth of a cancer cell. TCGA also biologically characterizes the tumors in several other ways. Together, the TCGA data can be linked to clinical data to help researchers understand the characteristics of the tumor being studied. The project plans to analyze up to 500 patient samples of tumors and normal tissues in 20 major types of cancer over the next five years.
"Cancer is a genetic disease," says NCI Director Dr. Harold Varmus. "Every discovery teaches us more and more about the many ways genes can be deranged in a tumor cell to make it grow out of control. While we generally describe some 200 types of cancer based on where they originate in the body, genetics may show us that there are thousands of different types, each requiring different treatments. Fortunately, we are now acquiring the tools we need to understand them and to make important progress."
Washington University is a TCGA participant and has pioneered the use of comprehensive, genome-wide approaches to study cancer. Although the AML study just reported was not part of TCGA, the Washington University team has donated nearly 200 AML samples for comprehensive genomic analysis to the TCGA program.
"This work represents the culmination of years of collaborative research that has focused on cataloging the mutations involved in AML," says study co-author Dr. John Dipersio, chief of the division of oncology and deputy director of the Siteman Cancer Center. "This work provides a pathway and a foundation for doing the same in all other malignancies that could potentially lead to more effective, targeted therapies."
The AML study was supported by funding from several NIH centers and institutes, including NHGRI, NCI and the National Center for Research Resources, as well as the Barnes-Jewish Hospital Foundation and Washington University.
