--First Finding of Origin of a Puzzling Pediatric Tumor--
PHILADELPHIA, May 7 /PRNewswire-USNewswire/ -- Using advanced
gene-hunting technology, an international team of researchers has for the
first time identified a chromosome region that is the source of genetic
events that give rise to neuroblastoma, an often fatal childhood cancer.
The investigators found that the presence of common DNA variations in a
region of chromosome 6 raises the risk that a child will develop a
particularly aggressive form of neuroblastoma, a cancer of the peripheral
nervous system that usually appears as a solid tumor in the chest or
abdomen. Neuroblastoma accounts for 7 percent of all childhood cancers, but
due to its aggressive nature, causes 15 percent of all childhood cancer
deaths.
"Until now we had very few clues as to what causes neuroblastoma," said
pediatric oncologist John M. Maris, M.D., who led the study at The
Children's Hospital of Philadelphia, where he is the director of the Center
for Childhood Cancer Research. "Although there is much work to be done,"
added Maris, "understanding this cancer's origin provides a starting point
for developing novel treatments." The study team reported its findings in
today's Online First version of the New England Journal of Medicine.
Neuroblastoma is the most common solid cancer of early childhood and
has long been known to include subtypes that behave very differently. Some
cases strike infants but spontaneously disappear with minimal treatment,
while other cases in older children may be relentlessly aggressive from the
start.
Researchers at Children's Hospital and colleagues in the multicenter
Children's Oncology Group have for decades analyzed tumors for
characteristics such as amplified levels of a cancer-causing gene and
deletions of chromosome material. They used those tumor peculiarities to
classify neuroblastoma into risk levels that guide oncologists toward the
most appropriate treatments. "Properly defining risk level helps us to
avoid the twin pitfalls of undertreating or overtreating any given child
with neuroblastoma," added Maris.
However, little was known about genetic events that predispose a child
to developing a neuroblastoma tumor. In roughly half of neuroblastoma
cases, the cancer is not discovered until it has spread widely in a
patient's body, so understanding how a tumor originates may allow
oncologists to design earlier and more successful interventions.
In the current study, Maris's team collaborated with Hakon Hakonarson,
M.D., Ph.D., director of Children's Hospital's Center for Applied Genomics,
to analyze blood samples from approximately 1,000 neuroblastoma patients,
as well as samples from some 2,000 healthy children recruited through the
Children's Hospital network. A DNA chip analysis performed at the genome
center identified three single nucleotide polymorphisms (SNPs) -- changes
in single bases on the DNA helix. Out of over 550,000 SNPs studied, those
SNPs were much more common in patients with neuroblastoma, compared to the
controls. The three SNPs occurred together on a band of chromosome 6
designated 6p22.
The researchers repeated the analysis in blood samples from additional
groups of patients and control subjects from the U.S. and the U.K., and
confirmed their finding that variants in the 6p22 region were implicated in
neuroblastoma. There are two genes in the 6p22 region, but their functions
are largely unknown.
"We are doing further studies to understand how these relatively common
genetic changes translate into increased risk of cancer," said Maris.
"Ultimately, they probably cause subtle changes in gene expression during
early development, interacting with other genes yet to be discovered. This
suggests that neuroblastoma has complex causes, in which a series of
genetic changes may occur at different sites to combine into a 'perfect
storm' that results in this cancer."
The researchers found that patients with these at-risk SNPs on
chromosome 6 were more likely to develop aggressive neuroblastoma. The
initial changes on chromosome 6 in all their body cells eventually led to
the genetic abnormalities seen in tumor cells in high-risk forms of the
disease.
Because their finding reveals only the first step in a series of
molecular events, added Maris, it would be premature to do prenatal genetic
testing for the SNPs on chromosome 6. His research team will continue to
perform genetic analyses, in search of other gene changes that interact
with those SNPs. One data source will be 5,000 tissue samples in Maris's
lab -- the world's largest collection of neuroblastoma samples, drawing on
decades of research into the disease by Maris, his colleagues and
predecessors at Children's Hospital.
"This discovery lays the foundation for learning how these initial
changes influence biological pathways that lead to neuroblastoma," added
Maris. "Understanding those pathways may guide us to new and better
therapies that precisely target this cancer." Hakonarson added, "This study
represents one of many ongoing projects to which scientists at The
Children's Hospital of Philadelphia are committed, and we anticipate
several comparable discoveries will be made in other common and equally
complex pediatric disorders, such as autism, asthma, ADHD and diabetes."
The National Institutes of Health supported the study, along with
grants from the Alex's Lemonade Stand Foundation, the Center for Applied
Genomics, the Abramson Family Cancer Research Institute and the Institute
of Cancer Research, located in the U.K.
Among Maris's and Hakonarson's co-authors were several collaborators
from The Children's Hospital of Philadelphia and the University of
Pennsylvania School of Medicine; the Institute of Cancer Research in
Surrey, U.K.; the University of Birmingham, U.K.; the University Federico
II, Naples, Italy; the University of Rome; the Children's Hospital of Los
Angeles; and the University of Florida.
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.
SOURCE The Children's Hospital of Philadelphia
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Related links:
http://www.chop.edu
CONTACT:
Rachel Salis-Silverman of The Children's
Hospital of Philadelphia, +1-267-426-6063, Salis@email.chop.edu
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