November 15, 2015
A team of pediatric cancer researchers at Children's Hospital of Philadelphia have identified a single change to one DNA base that predisposes children to an aggressive form of the childhood cancer neuroblastoma, accelerating the progression of the disease once tumors form.
When the LMO1 gene undergoes the change, known as a single-nucleotide polymorphism (SNP), the gene acts a "super-enhancer" of abnormal biological activity, according to a news release. The increased activity of the gene worsens the formation and progression of tumors.
“Cancers in general, and neuroblastoma in particular, have complex origins,” said John M. Maris, MD, a pediatric oncologist at (CHOP) and senior author of the paper published in the journal Nature. “It’s not common to discover causal gene variants in cancer, especially in a single base within the DNA sequence such as this.”
To reach their findings, Maris and his colleagues expanded on a 2011 genome-wide association study, which showed a link between common SNPs and increased neuroblastoma susceptibility. Because gene transcription becomes abnormally altered, the researchers sought to find the exact location, variation and molecular process that occurs in the genome.
Specifically, gene-mapping studies determined that the presence of the DNA base guanine drives the super-enhancer activity by revving up LMO1 expression. Conversely, if the base is thymine, children are better protected against neuroblastoma, an adaptation believed to have come following human migration from Africa thousands of years ago.
Neuroblastoma, the most common form of cancer in infants, affects the peripheral nervous system and usually appears as a solid tumor in the chest or abdomen. While the discovery does not offer any immediate treatment options – no existing drugs counter the abnormal functioning of LMO1-driven neuroblastoma – it could point the way toward new therapeutic approaches by enabling a better grasp of molecular events.
The research at CHOP was primarily funded by grants from the National Institutes of Health, the Press on Foundation, Andrew's Army Foundation, Alex's Lemonade Stand Foundation and the Brooke Mulford Foundation.
