Researchers Discover Key Mutation in Acute Myeloid Leukemia
Posted Nov 11 2010 6:14pm
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 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."
Launched in 2006 as a partnership between the National Cancer Institute
and the National Human Genome Research Institute, both NIH components,
The Cancer Genome Atlas (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," said NCI Director Harold Varmus,
M.D. "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
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. The AML results and all TCGA analyses can be found
at its data portal, http://cancergenome.nih.gov/dataportal ,
which provides direct access to the genomic analytic datasets, with selected
patient genetic and clinical data to researchers qualified through an
NIH review and approval process designed to safeguard participant privacy.
"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, M.D., Ph.D., 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.
AML is a cancer of the blood. Like most cancers, it develops from mutations
that occur in cells over the course of many years during a persons life
and not from inherited genetic errors present at birth. AML strikes some
13,000 Americans annually, killing 9,000. 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 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
Washington University School of Medicine's 2,100 employed and volunteer
faculty physicians also are the medical staff of Barnes-Jewish and St.
Louis Children's hospitals. The School of Medicine is one of the leading
medical research, teaching and patient care institutions in the nation.
Through its affiliations with Barnes-Jewish and St. Louis Children's
hospitals, the School of Medicine is linked to BJC HealthCare.
NCI leads the National Cancer Program and the NIH effort to dramatically
reduce the burden of cancer and improve the lives of cancer patients
and their families, through research into prevention and cancer biology,
the development of new interventions, and the training and mentoring
of new researchers. For more information about cancer, please visit the
NCI Web site at http://www.cancer.gov or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
NHGRI is one of the 27 institutes and centers at the NIH. The NHGRI
Division of Extramural Research supports grants for research and for
training and career development. Additional information about NHGRI can
be found at its website, www.genome.gov .
The National Institutes of Health (NIH) — The Nation's Medical
Research Agency — includes 27 Institutes and Centers and is
a component of the U.S. Department of Health and Human Services. It is
the primary federal agency for conducting and supporting basic, clinical
and translational medical research, and it investigates the causes, treatments,
and cures for both common and rare diseases. For more information about
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