An inherited gene variation has been linked to a nearly fourfold increased risk of developing a pediatric acute lymphoblastic leukemia (ALL) subtype that is associated with a poor outcome. This study was published in Nature Genetics (2013; doi:10.1038/ng.2803).

The high-risk variant was found in the GATA3 gene, and its high-risk version was more common among Hispanic Americans and other persons with high Native American ancestry than those with other ethnic backgrounds. A total of 40% of Hispanic Americans carried the high-risk variant, compared with 14% of persons of European ancestry. This study defined ancestry by genetic variations associated with ancestry rather than individual self-reports.

Hispanic children are known to be at a higher risk for developing ALL and of dying from the disease, which is the most common childhood cancer. This is the latest in a series of studies by St. Jude Children’s Research Hospital, in Memphis, Tennessee, to report an association between inherited DNA variations in a handful of genes and an increased risk of childhood ALL among those of Hispanic ethnicity.

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This is the first study to link an inherited genetic variation to an elevated risk of developing the leukemia subtype known as Philadelphia chromosome-like ALL (Ph-like ALL). People with the high-risk version of GATA3 were 3.85 times more likely than those who inherited a different version of the gene to develop Ph-like ALL. Patients with the high-risk variant were also more likely to have a poor response to treatment and have their cancer eventually return.

A significant percentage of patients with the high-risk GATA3 variant also had the tumor genetic alterations—including mutations, gene deletions, and chromosomal re-arrangements—that are hallmarks of Ph-like ALL.

Ph-like ALL accounts for as much as 15% of childhood ALL and is associated with a high risk of relapse and a poor outcome. Although overall cure rates for pediatric ALL are now about 90%, only 63% of children with Ph-like ALL are alive and cancer free after 5 years.

“Until recently, little was known about why a child develops a specific subtype of ALL in the first place and whether inherited genetic variations that predispose an individual to a subtype also influence how he or she responds to the therapy,” said Jun J. Yang, PhD, of St. Jude. “In this study, we discovered a genetic basis for susceptibility to Ph-like ALL, but even more importantly, the evidence that host and tumor genomes may interact with each other to influence the risk of developing and surviving ALL.”

GATA3 carries instructions for assembling a protein called a transcription factor that turns other genes on and off. The GATA3 protein, and other members of the GATA gene family, plays a crucial role in normal development of a variety of blood cells.

“Because this variant causes higher expression of GATA3 from birth, we suspect that this increased level of GATA3 may set the stage for developing Ph-like ALL later,” said Virginia Perez-Andreu, MD, PhD, a St. Jude postdoctoral fellow.