2 gene mutations I.D.'d in neuroblastoma, says researcher from the Children's Hospital of Philadelphia
Using powerful gene-analysis tools, researchers have discovered mutations in two related genes, ARID1A and ARID1B, that are involved in the most aggressive form of the childhood cancer neuroblastoma. While these findings do not immediately improve clinical treatments, they identify a novel pathway that is defective in these cancers, a pathway that scientists can now study to develop potential new therapies.
"These gene alterations were not previously known to be mutated in neuroblastoma, and they may significantly advance our knowledge of the underlying biological pathways that drive this disease," said study leader Michael D. Hogarty, M.D., a pediatric oncologist at The Children's Hospital of Philadelphia. "These two genes function in a group of genes that seems to play an important role in neural cell behavior, and we will now work to discover if this insight may open up new treatments for children with tumors having these mutations."
Hogarty, along with Victor Velculescu, M.D., Ph.D., of the Johns Hopkins Kimmel Cancer Center, co-led the study that appeared today in Nature Genetics.
The scientists received over $1 million in funding from the St. Baldrick's Foundation, a volunteer-driven and donor-centered charity dedicated to raising money for childhood cancer research.
The current study employed sophisticated next-generation sequencing technology that identified the entire DNA sequence for a set of neuroblastoma tumors. "When this project started, it was the first of its kind to focus on a childhood tumor," said Hogarty. "This is important, because cataloguing all the DNA mutations in neuroblastoma, or any tumor, will allow us to better understand the enemy, and ultimately to make better treatment decisions."
Striking the peripheral nervous system, neuroblastoma usually appears as a solid tumor in the chest or abdomen of young children. It accounts for 7 percent of all childhood cancers, but 10 to 15 percent of all childhood cancer-related deaths.
In the current study, Hogarty and colleagues identified alterations in two genes, ARID1A and ARID1B, neither of which had previously been reported to be involved in neuroblastoma. Both genes are thought to affect chromatin, a combination of DNA and protein that regulates the activities of genes and ultimately controls the behavior of a cell. During normal development, neural cells switch from a primitive, rapidly dividing state (neuroblasts) into a more differentiated, or mature state (neurons).
However, said Hogarty, mutations in ARID1A and ARID1B may prevent this orderly transition, keeping the neural cells in the uncontrolled stage of growth that becomes a cancerous tumor. "Unfortunately, children with these mutations have a particularly aggressive, treatment-resistant form of neuroblastoma," he added. The current study found that ARID1A and ARID1B mutations occur in 5 to 15 percent of high-risk neuroblastomas, but the pathway these genes affect may have a broader role in the disease—a possibility that Hogarty and colleagues plan to investigate further. It is possible that children having tumors with these mutations will receive more aggressive or more experimental treatments in the future.
Ultimately, said Hogarty, studies of the pathway affected by these genes may lay the foundation for future targeted therapies aimed at this pathway.
In the current study, the scientists also developed an approach that detects the tumor DNA abnormalities in the blood. "All tumors harbor genetic mistakes that leave a fingerprint in the DNA, and tumor DNA is often detected in the blood as well," he explained. "We may be able to develop a blood test, personalized to each cancer patient, to detect their tumor fingerprint in circulating blood DNA. This would permit oncologists to more accurately monitor patients for treatment response and recurrence, and offer a tool to help guide treatment decisions."
In addition to funding from St. Baldrick's, this study also received support from the National Institutes of Health (grant CA121113), the Children's Oncology Group, the Virginia and D.K. Ludwig Fund for Cancer Research, Swim Across America, and the AACR Stand Up to Cancer-Dream Team Translational Cancer Research Grant.
"Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma," Nature Genetics, advance online publication, Dec. 2, 2012. doi: 10.1038/ng.2493
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 516-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.
Rachel Salis-Silverman | Source: EurekAlert!
Further information: www.chop.edu
Further Reports about: ARID1A > ARID1B > childhood cancer > DNA > DNA mutation > gene mutation > gene-sequencing tools > Genetics > health services > Nature Genetics > Nature Immunology > neural cells > powerful gene-analysis tools
More articles from Life Sciences:
ASU researchers discover chameleons use colorful language to communicate
12.12.2013 | Arizona State University
Sleep-deprived mice show connections among lack of shut-eye, diabetes, age
12.12.2013 | University of Pennsylvania School of Medicine
A unique solar panel design made with a new ceramic material points the way to potentially providing sustainable power cheaper, more efficiently, and requiring less manufacturing time.
It also reaches a four-decade-old goal of discovering a bulk photovoltaic material that can harness energy from visible and infrared light, not just ultraviolet light.
Scaling up this new design from its tablet-size prototype to a full-size solar panel would be a large step toward making solar power affordable compared with ...
Atlantische Flohkrebse pflanzen sich jetzt auch in arktischen Gewässern fort
Biologen des Alfred-Wegener-Institutes, Helmholtz-Zentrum für Polar- und Meeresforschung (AWI), haben zum ersten Mal nachgewiesen, dass sich in den arktischen Gewässern westlich Spitzbergens auch Flohkrebse aus dem wärmeren Atlantik fortpflanzen.
Diese überraschende Entdeckung deute auf einen möglichen Wandel der arktischen Zooplankton-Gemeinschaft hin, berichten die Wissenschaftler und Wissenschaftlerinnen in der Fachzeitschrift Marine Ecology ...
The molecular architecture of three key proteins and their complexes reveals how plants fine-tune their immune response to pathogens
Plants rarely get sick in their natural environment. When the threat of infection arises, a quick decision is made about the necessary countermeasures. The course is set by a protein which forms complexes with its partner proteins for this purpose.
Jane Parker from the Max Planck Institute for Plant Breeding ...
Researchers studying speciation of butterfly orchids on the Azores have been startled to discover that the answer to a long-debated question "Do the islands support one species or two species?" is actually "three species".
Hochstetter's Butterfly-orchid, newly recognized following application of a battery of scientific techniques and reveling in a complex taxonomic history worthy of Sherlock Holmes, is arguably Europe's rarest orchid species. Under threat in its mountain-top retreat, the orchid urgently requires conservation recognition.
A lavishly illustrated publication, titled "Systematic revision of Platanthera in ...
Researchers from Brown University and the University of Hawaii have found some mineralogical surprises in the Moon's largest impact crater.
Data from the Moon Mineralogy Mapper that flew aboard India's Chandrayaan-1 lunar orbiter shows a diverse mineralogy in the subsurface of the giant South Pole Aitken basin.
The differing mineral signatures could be reflective of the minerals dredged up at the time of the giant impact 4 billion years ago, ...
12.12.2013 | Life Sciences
12.12.2013 | Earth Sciences
12.12.2013 | Studies and Analyses
11.12.2013 | Event News
10.12.2013 | Event News
05.12.2013 | Event News