Genome Scans Find Clues to Childhood Cancer
In the first genome-wide association study of a rare cancer, researchers have identified common genetic variants that may increase the risk of neuroblastoma, a childhood cancer of the nervous system.
Risk factors for the more aggressive forms of neuroblastoma may reside on a region of chromosome 6, according to a report published online last week in the New England Journal of Medicine (NEJM). The region was not previously linked to the disease.
Little has been known about susceptibility to neuroblastoma. The disease often begins in early childhood (or before birth) and initially affects the nerve tissue of the adrenal glands. Many researchers have thought that mutations in several major genes would largely determine the inherited component of the disease.
The new results suggest that different types of genetic changes, including some common variations, contribute to susceptibility. The findings also suggest that it should be possible to identify the common risk factors using genome scans, according to the researchers.
"This study is an important proof of concept," said lead investigator Dr. John Maris of the Children's Hospital of Philadelphia. "There was a real possibility before we began that we might not find any common variants, but the results clearly show that common genetic variants contribute to the risk of neuroblastoma."
Neuroblastoma remains one of the most challenging childhood cancers. More than 90 percent of patients with localized neuroblastomas survive, even when regional lymph nodes are affected. But more than half of all patients have a more aggressive form of the disease that is often fatal.
There are approximately 700 cases in the United States each year, yet despite these small numbers, the study was large. DNA came from 1,700 neuroblastoma patients and twice as many children without the disease. The patient samples had been collected over a decade by the NCI-sponsored Children's Oncology Group.
The researchers plan to analyze up to 5,000 neuroblastoma patients in the coming years. They are also investigating other types of genetic variation, such as changes in the number of copies of genes. Preliminary results suggest that these also play a role.
"There clearly are other variants that we have not found yet," said Dr. Hakon Hakonarson of Children's Hospital of Philadelphia and the report's senior author. "This is an ongoing study, and our hope is to identify the bulk of the underlying genetic factors that predispose to neuroblastoma."
The chromosome 6 variants - which include three single nucleotide polymorphisms (SNPs), or single-letter changes in genetic code - occur in two overlapping genes. The researchers are "re-sequencing" the entire region to identify the precise source of the risk.
The absolute risk conferred by the chromosome 6 variants is extremely small, and therefore these SNPs, on their own, would be of little value in screening.
"This is a terrific study," said Dr. Stephen Chanock of NCI's Division of Cancer Epidemiology and Genetics, who was not an author. "Many have thought that the genetics of rare childhood diseases would be explained by a couple of rare mutations, but this study tells us that the genomic architecture is complex and that different types of genetic variation play a role."
Neuroblastoma could offer researchers a rare opportunity to study the interactions of genes and environmental factors in a complex disease, Dr. Chanock added, noting the relatively short time between conception and the development of the cancer.
—Edward R. Winstead