Discovery of gene location that gives rise to neuroblastoma, an aggressive childhood cancer

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

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

“Until now we had very few clues as to what causes neuroblastoma,” said paediatric oncologist John M. Maris, M.D., who led the study at The Children’s Hospital of Philadelphia, US, where he is the director of the Centre for Childhood Cancer Research. “Although there is much work to be done,” added Maris, “understanding this cancer’s origin provides a starting point for developing novel treatments.” The study team reported its findings in the New England Journal of Medicine.

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

Researchers at Children’s Hospital and colleagues in the multi centre Children’s Oncology Group have for decades analysed tumours for characteristics such as amplified levels of a cancer-causing gene and deletions of chromosome material. They used those tumour peculiarities to classify neuroblastoma into risk levels that guide oncologists toward the most appropriate treatments. “Properly defining risk level helps us to avoid the twin pitfalls of undertreating or overtreating any given child with neuroblastoma,” added Maris.

However, little was known about genetic events that predispose a child to developing a neuroblastoma tumour. In roughly half of neuroblastoma cases, the cancer is not discovered until it has spread widely in a patient’s body, so understanding how a tumour originates may allow oncologists to design earlier and more successful interventions.
In the current study, Maris’s team collaborated with Hakon Hakonarson, M.D., Ph.D., director of Children’s Hospital’s Centre for Applied Genomics, to analyse blood samples from approximately 1,000 neuroblastoma patients, as well as samples from some 2,000 healthy children recruited through the Children’s Hospital network. A DNA chip analysis performed at the genome centre identified three single nucleotide polymorphisms (SNPs)—changes in single bases on the DNA helix. Out of over 550,000 SNPs studied, those SNPs were much more common in patients with neuroblastoma, compared to the controls. The three SNPs occurred together on a band of chromosome 6 designated 6p22.

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

“We are doing further studies to understand how these relatively common genetic changes translate into increased risk of cancer,” said Maris. “Ultimately, they probably cause subtle changes in gene expression during early development, interacting with other genes yet to be discovered. This suggests that neuroblastoma has complex causes, in which a series of genetic changes may occur at di