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Gene-Sequencing Applications Developed for Highest-Risk form of a Childhood Cancer

By BiotechDaily International staff writers
Posted on 17 Dec 2012
Using cutting-edge gene-analysis tools, researchers have found mutations in two related genes, ARID1A and ARID1B, which are involved in neuroblastoma, a childhood cancer that is extremely aggressive. While this new research does not improve clinical treatments right now, they identify a unique pathway that is defective in these cancers, a pathway that investigators can now research 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, MD, a pediatric oncologist at The Children’s Hospital of Philadelphia (PA, USA). “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.”

Dr. Hogarty, along with Victor Velculescu, MD, PhD, of the Johns Hopkins Kimmel Cancer Center (Baltimore, MD, USA), co-led the study that was published December 2, 2012, in the journal Nature Genetics. The current study employed cutting edge, next-generation sequencing technology that identified the complete DNA sequence for a range of neuroblastoma tumors. “When this project started, it was the first of its kind to focus on a childhood tumor,” said Dr. Hogarty. “This is important, because cataloging all the DNA mutations in neuroblastoma, or any tumor, will allow us to better understand the enemy, and ultimately to make better treatment decisions.”

Targeting the peripheral nervous system, neuroblastoma typically presents as a solid tumor in the abdomen or chest of young children. It accounts for 7% of all childhood cancers, however, 10%–15% of all childhood cancer-related deaths. In the current study, Dr. Hogarty and colleagues identified two gene alterations, ARID1A and ARID1B, neither of which had earlier been reported to be involved in neuroblastoma. Both genes are believed to affect chromatin, a combination of protein and DNA that controls gene activity and ultimately controls the behavior of a cell. During normal development, neural cells switch from a primitive, quickly dividing state (neuroblasts) into a more differentiated, mature state (neurons).

Mutations in ARID1A and ARID1B, however, according to Dr. Hogarty may prevent this methodical 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. This research revealed that ARID1A and ARID1B mutations occur in 5%–15% of high-risk neuroblastomas, but the pathway these genes affect may have a more wide-ranging role in the disease—a possibility that Dr. 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.

Eventually, reported Dr. Hogarty, more research of the pathway affected by these genes will help for future targeted therapies geared 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 clarified. “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.”

Related Links:
Children’s Hospital of Philadelphia
Johns Hopkins Kimmel Cancer Center


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