Using powerful gene-analysis tools, The Children's Hospital of Philadelphia 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, MD, a pediatric oncologist at Children's Hospital. Dr. Hogarty, along with Victor Velculescu, MD, PhD, of the Johns Hopkins Kimmel Cancer Center, co-led the study that appeared recently in Nature Genetics.
In the current study, the investigators 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 Dr. 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. The 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 the researchers 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, studies of the pathway affected by these genes may lay the foundation for future targeted therapies aimed at this pathway. The investigators also developed an approach that detects the tumor DNA abnormalities in the blood.