--May Lead to New Prevention and Treatment Strategies--
PHILADELPHIA, Aug. 25 /PRNewswire-USNewswire/ -- Scientists have
discovered gene mutations that are the main cause of the inherited version
of the childhood cancer neuroblastoma. In addition, the researchers found
that the same mutations play a significant role in high-risk forms of
non-inherited neuroblastoma, the more common form of the disease.
"This discovery enables us to offer the first genetic tests to families
affected by the inherited form of this disease," said pediatric oncologist
Yael P. Mosse, M.D., of The Children's Hospital of Philadelphia, the first
author of the study, published online Aug. 24 in the journal Nature.
"Furthermore, because there already are drugs in development that target
the same gene in adult cancers, we can soon begin testing those drugs in
children with neuroblastoma."
Neuroblastoma is the most common solid cancer of early childhood. It
accounts for 7 percent of all childhood cancers, but due to its often
aggressive nature, causes 15 percent of all childhood cancer deaths. It
arises in the developing nerves of a child, often appearing as a tumor in
the chest or abdomen.
Because only about 600 new cases of all forms of neuroblastoma occur
annually in the U.S., familial (inherited) neuroblastoma is a very rare
subset of a relatively uncommon disease. Scientists at Children's Hospital
have studied familial neuroblastoma for the past 15 years, and the current
study drew on family data collected from throughout the world.
John M. Maris, M.D., senior author of the current study and director of
the Center for Childhood Cancer Research at Children's Hospital, leads a
laboratory with the world's largest collection of neuroblastoma tissue
samples, gathered through the multicenter Children's Oncology Group in the
U.S. and through multiple international collaborations. Maris said, "This
is a very important discovery, as it not only helps us understand the
genetic roots of this terrible disease, but also has led to dramatically
new ideas for curative therapy."
The study team used high-speed, automated analytic equipment at the
Center for Applied Genomics at Children's Hospital. By employing
genome-wide scans to analyze DNA from the 10 most informative families with
a history of neuroblastoma, Mosse and her colleagues first discovered that
a region of chromosome 2 was associated with the disease. Further
sequencing of that region identified mutations in the anaplastic lymphoma
kinase (ALK) gene in eight families with familial neuroblastoma.
"This finding means that it is possible to offer simple, non-invasive
screening for patients with a family history of neuroblastoma," said Mosse.
She explained that ultrasound or a urine test could assist surveillance of
children with an ALK mutation, so that if neuroblastoma appears, it can be
detected at an early stage. "As we increase our knowledge of ALK mutations,
we will also offer specialized diagnostic testing for all newly diagnosed
patients with neuroblastoma, to eventually allow oncologists to better
customize treatment to a child's genetic profile."
After detecting ALK mutations in familial neuroblastoma, the
researchers then focused on the more common sporadic (non-familial) cases
of neuroblastoma, and found that ALK mutations occurred in 12 percent of
194 tumor samples from the aggressive, high-risk form of the disease.
Although the normal role of the ALK gene is not well understood, other
researchers had previously found that abnormalities in ALK raise a
patient's risk for lymphoma and lung cancer. "We were the first to identify
mutations in ALK," said Mosse, adding that in lymphoma and lung cancer, ALK
acts through translocation, a different mechanism that involves an exchange
of DNA between chromosomes to produce a new cancer-causing fusion gene.
In all three cancers, ALK acts as an oncogene, or cancer-causing gene;
in fact, the current study reports the first example of a childhood cancer
caused by mutations in an oncogene. Since the mutations discovered by Mosse
trigger an "on" signal for neuroblastoma cells, the abnormality is an
outstanding target for therapies that inhibit the ALK protein's activity.
Several pharmaceutical companies are currently developing ALK
inhibitors in the laboratory, and one ALK inhibitor is already in
early-phase adult clinical trials against lung cancer and lymphoma. Now
Mosse and her colleagues at Children's Hospital are planning pediatric
clinical trials of ALK inhibitors in children with high-risk neuroblastoma.
"It's an advantage to be able to start with agents that have already been
shown to be safe in adults," Mosse added.
Neuroblastoma has long been a puzzling disease, partly because of its
broad range in outcomes. Some types of the disease strike infants but
spontaneously disappear with minimal treatment, while other subtypes in
older children may be relentlessly aggressive. Earlier this year, Maris's
lab reported that common DNA variations in a region of chromosome 6 raise a
child's risk of developing sporadic neuroblastoma. "Together with this
current study, we are defining the genetic events that underlie this
childhood cancer," said Maris. "Better understanding of these biological
pathways will guide our efforts to develop more effective treatments."
The National Institutes of Health supported the study, along with
grants from the Alex's Lemonade Stand Foundation, the American Society of
Clinical Oncology, the Andrew's Army Foundation, the Italian Neuroblastoma
Foundation, Scripps Genomic Medicine, the Scripps Dickinson Scholarship,
the Giulio D'Angio Endowed Chair, the Foerderer-Murray Fund and the Carly
Hillman Fund. The Center for Applied Genomics at The Children's Hospital of
Philadelphia also provided support, as did the Abramson Family Cancer
Research Institute of the University of Pennsylvania School of Medicine.
The study could not have been done, say the authors, without the support
and resources of the Children's Oncology Group.
Among Mosse's and Maris's co-authors were Garrett M. Brodeur, M.D., of
the Division of Oncology and Center for Childhood Cancer Research at
Children's Hospital, as well as Hakon Hakonarson, M.D., Ph.D., director of
the Center for Applied Genomics at Children's Hospital. The above
co-authors are also faculty members of the University of Pennsylvania
School of Medicine. Other collaborators were from the National Institute
for Cancer Research, Genoa, Italy; Ghent University Hospital, Ghent,
Belgium; Scripps Research Institute, La Jolla, Calif.; and the University
of Rome "La Sapienza."
About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric
hospital. Through its long-standing commitment to providing exceptional
patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's
Hospital has fostered many discoveries that have benefited children
worldwide. Its pediatric research program is among the largest in the
country, ranking third in National Institutes of Health funding. In
addition, its unique family-centered care and public service programs have
brought the 430-bed hospital recognition as a leading advocate for children
and adolescents. For more information, visit http://www.chop.edu.
Contact: Rachel Salis-Silverman
Phone: (267) 426-6063
Salis@email.chop.edu
SOURCE The Children's Hospital of Philadelphia
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http://www.chop.edu
CONTACT:
Rachel Salis-Silverman of The Children's
Hospital of Philadelphia, +1-267-426-6063, mobile:
+1-267-970-3685, Salis@email.chop.edu
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