From: Subject: Researchers find gene location that gives rise to neuroblastoma, an aggressive childhood cancer Date: Tue, 13 May 2008 16:55:27 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0016_01C8B51A.24E71400" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5512 This is a multi-part message in MIME format. ------=_NextPart_000_0016_01C8B51A.24E71400 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.eurekalert.org/pub_releases/2008-05/chop-rfg050208.php Researchers find gene location that gives rise to = neuroblastoma, an aggressive childhood cancer 3D"[ Public = release date:=20 7-May-2008
[ | E-mail Article ]

Contact: Rachel Salis-Silverman
Salis@email.chop.edu
267-426-= 6063
Children's Hospital of=20 Philadelphia

Researchers find gene location that gives rise to = neuroblastoma,=20 an aggressive childhood cancer

First finding of origin of a puzzling pediatric = tumor

Using advanced gene-hunting technology, an international team of = researchers=20 has for the first time identified a chromosome region that is the source = of=20 genetic events that give rise to neuroblastoma, an often fatal childhood = cancer.=20

The investigators found that the presence of common DNA variations in = a=20 region of chromosome 6 raises the risk that a child will develop a = particularly=20 aggressive form of neuroblastoma, a cancer of the peripheral nervous = system that=20 usually appears as a solid tumor in the chest or abdomen. Neuroblastoma = accounts=20 for 7 percent of all childhood cancers, but due to its aggressive = nature, causes=20 15 percent of all childhood cancer deaths.

=93Until now we had very few clues as to what causes = neuroblastoma,=94 said=20 pediatric oncologist John M. Maris, M.D., who led the study at The = Children=92s=20 Hospital of Philadelphia, where he is the director of the Center for = Childhood=20 Cancer Research. =93Although there is much work to be done,=94 added = Maris,=20 =93understanding this cancer=92s origin provides a starting point for = developing=20 novel treatments.=94 The study team reported its findings in today=92s = Online First=20 version of the New England Journal of Medicine.

Neuroblastoma is the most common solid cancer of early childhood and = has long=20 been known to include subtypes that behave very differently. Some cases = strike=20 infants but spontaneously disappear with minimal treatment, while other = cases in=20 older children may be relentlessly aggressive from the start.

Researchers at Children=92s Hospital and colleagues in the = multicenter=20 Children=92s Oncology Group have for decades analyzed tumors for = characteristics=20 such as amplified levels of a cancer-causing gene and deletions of = chromosome=20 material. They used those tumor peculiarities to classify neuroblastoma = into=20 risk levels that guide oncologists toward the most appropriate = treatments.=20 =93Properly defining risk level helps us to avoid the twin pitfalls of=20 undertreating or overtreating any given child with neuroblastoma,=94 = added=20 Maris.

However, little was known about genetic events that predispose a = child to=20 developing a neuroblastoma tumor. In roughly half of neuroblastoma = cases, the=20 cancer is not discovered until it has spread widely in a patient=92s = body, so=20 understanding how a tumor originates may allow oncologists to design = earlier and=20 more successful interventions.

In the current study, Maris=92s team collaborated with Hakon = Hakonarson, M.D.,=20 Ph.D., director of Children=92s Hospital=92s Center for Applied = Genomics, to analyze=20 blood samples from approximately 1,000 neuroblastoma patients, as well = as=20 samples from some 2,000 healthy children recruited through the = Children=92s=20 Hospital network. A DNA chip analysis performed at the genome center = identified=20 three single nucleotide polymorphisms (SNPs)=97changes in single bases = on the DNA=20 helix. Out of over 550,000 SNPs studied, those SNPs were much more = common in=20 patients with neuroblastoma, compared to the controls. The three SNPs = occurred=20 together on a band of chromosome 6 designated 6p22.

The researchers repeated the analysis in blood samples from = additional groups=20 of patients and control subjects from the U.S. and the U.K., and = confirmed their=20 finding that variants in the 6p22 region were implicated in = neuroblastoma. There=20 are two genes in the 6p22 region, but their functions are largely = unknown.

=93We are doing further studies to understand how these relatively = common=20 genetic changes translate into increased risk of cancer,=94 said Maris.=20 =93Ultimately, they probably cause subtle changes in gene expression = during early=20 development, interacting with other genes yet to be discovered. This = suggests=20 that neuroblastoma has complex causes, in which a series of genetic = changes may=20 occur at different sites to combine into a =91perfect storm=92 that = results in this=20 cancer.=94

The researchers found that patients with these at-risk SNPs on = chromosome 6=20 were more likely to develop aggressive neuroblastoma. The initial = changes on=20 chromosome 6 in all their body cells eventually led to the genetic = abnormalities=20 seen in tumor cells in high-risk forms of the disease.

Because their finding reveals only the first step in a series of = molecular=20 events, added Maris, it would be premature to do prenatal genetic = testing for=20 the SNPs on chromosome 6. His research team will continue to perform = genetic=20 analyses, in search of other gene changes that interact with those SNPs. = One=20 data source will be 5,000 tissue samples in Maris=92s lab=97the = world=92s largest=20 collection of neuroblastoma samples, drawing on decades of research into = the=20 disease by Maris, his colleagues and predecessors at Children=92s = Hospital.

=93This discovery lays the foundation for learning how these initial = changes=20 influence biological pathways that lead to neuroblastoma,=94 added = Maris.=20 =93Understanding those pathways may guide us to new and better therapies = that=20 precisely target this cancer.=94 Hakonarson added, =93This study = represents one of=20 many ongoing projects to which scientists at The Children=92s Hospital = of=20 Philadelphia are committed, and we anticipate several comparable = discoveries=20 will be made in other common and equally complex pediatric disorders, = such as=20 autism, asthma, ADHD and diabetes.=94

###

The National Institutes of Health supported the study, along with = grants from=20 the Alex=92s Lemonade Stand Foundation, the Center for Applied Genomics, = the=20 Abramson Family Cancer Research Institute and the Institute of Cancer = Research,=20 located in the U.K.

Among Maris=92s and Hakonarson=92s co-authors were several = collaborators from The=20 Children=92s Hospital of Philadelphia and the University of Pennsylvania = School of=20 Medicine; the Institute of Cancer Research in Surrey, U.K.; the = University of=20 Birmingham, U.K.; the University Federico II, Naples, Italy; the = University of=20 Rome; the Children=92s Hospital of Los Angeles; and the University of = Florida.=20

About The Children=92s Hospital of Philadelphia: The Children's = Hospital of=20 Philadelphia was founded in 1855 as the nation's first pediatric = hospital.=20 Through its long-standing commitment to providing exceptional patient = care,=20 training new generations of pediatric healthcare professionals and = pioneering=20 major research initiatives, Children=92s Hospital has fostered many = discoveries=20 that have benefited children worldwide. Its pediatric research program = is among=20 the largest in the country, ranking third in National Institutes of = Health=20 funding. In addition, its unique family-centered care and public service = programs have brought the 430-bed hospital recognition as a leading = advocate for=20 children and adolescents. For more information, visit http://www.chop.edu/.


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