Alterations in two genes involved in highest-risk form of childhood cancer

Using powerful gene-analysis tools, researchers have discovered mutations in two related genes, ARID1A and ARID1B, which 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 paediatric 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 behaviour, and we will now work to discover if this insight may open up new treatments for children with tumours having these mutations.”

Hogarty, along with Victor Velculescu, MD, PhD, of the Johns Hopkins Kimmel Cancer Centre, 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-centred 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 tumours. “When this project started, it was the first of its kind to focus on a childhood tumour,” said Hogarty. “This is important, because cataloguing all the DNA mutations in neuroblastoma, or any tumour, 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 tumour in the chest or abdomen of young children. It accounts for 7% of all childhood cancers, but 10 to 15 per cent 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 behaviour 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 oAir Jordan