Identification of Mutations Linked to Neuroblastoma May Lead to New Therapeutic Approach

Development of neuroblastoma, the most common form of childhood cancer, has been linked to defects in two genes: an over expressed oncogene and an under expressed tumor suppressor gene.

Neuroblastoma is a cancer of the sympathetic nervous system that accounts for about 7% of all childhood cancers and 10 to 15% of all childhood cancer deaths. In order to identify genomic factors related to development of the disease investigators at Children's Hospital of Philadelphia (PA, USA; www.chop.edu) conducted a genome-wide association study (GWAS) of 2,817 neuroblastoma cases and 7,473 controls.

The investigators reported in the September 2, 2012, online edition of the journal Nature Genetics that they had identified two common gene variants associated with neuroblastoma, one in the HACE1 gene and the other in the LIN28B gene, both in the 6q16 region of chromosome 6.

The results showed that low expression of HACE1, a tumor suppressor gene, and high expression of LIN28B, an oncogene, correlated with worse patient survival. These findings were confirmed by studies on cultures of cancer cells that had been genetically engineered to lack LIN28B activity. Depletion of LIN28B caused significant growth inhibition in neuroblastoma cell cultures, especially those that were homozygous for the risk allele.

“We discovered common variants in the HACE1 and LIN28B genes that increase the risk of developing neuroblastoma. For LIN28B, these variants also appear to contribute to the tumor’s progression once it forms,” said first author Dr. Sharon J. Diskin, a pediatric cancer researcher at The Children’s Hospital of Philadelphia. “HACE1 and LIN28B are both known cancer-related genes, but this is the first study to link them to neuroblastoma.”

“In addition to broadening our understanding of the heritable component of neuroblastoma susceptibility, we think this research may suggest new therapies,” said Dr. Diskin. “Our follow-up studies will focus on how we may intervene on these genes’ biological pathways to develop more effective treatments.”

Related Links:
Children's Hospital of Philadelphia