Hispanic children are at an increased risk for acute lymphoblastic leukemia (ALL) and are more likely to die of their disease when compared to any other racial or ethnic group. Previous research has suggested genetic components are behind the disparity, and last year researchers isolated the gene ARID5B thought to be responsible for the ALL statistics. Now, researchers say there is another gene variation responsible for an almost 4-fold risk increase for a particularly deadly subtype of ALL in Hispanic children.
According to new study results from St. Jude Children’s Research Hospital, 40 percent of Hispanics carry a variation found in the GATA3 gene that not only indicates a 4-fold risk of developing the leukemia subtype known as Philadelphia chromosome-like ALL (Ph-like ALL), but is also associated with a poor disease outcome.
“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,” corresponding author Jun J. Yang, Ph.D., an assistant member of the St. Jude Department of Pharmaceutical Sciences, said in a statement. “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.”
Hispanic children 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. Those same individuals also had what researchers identified as tumor genetic alterations like mutations, gene deletions and chromosomal re-arrangements that are classic presentations of Ph-like ALL. Those gene variations related to tumor growth were found in genes CRLF2, JAK and IKZF1 that regulate how blood cells grow and mature.
The findings are important as, according to researchers, overall cure rates for pediatric lymphoblastic leukemia are approximately 90 percent, yet only 63 percent of children with Ph-like ALL are alive and cancer free after five years. Patients with the high-risk gene variation of GATA3 have issues with turning other genes on and off, as GATA3 plays an important role in normal development of a variety of blood cells. Individuals with with the high-risk gene variation are not only at-risk for ALL and its dangerous subtype, Ph-like ALL, but are also at risk for other blood cancers like Hodgkin lymphoma.
“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 first author Virginia Perez-Andreu, M.D., Ph.D., a St. Jude postdoctoral fellow in the pharmaceutical sciences department.
The identification of GATA3 and ARID5B will hopefully assist in the development for more targeted treatment of lymphoblastic leukemia and it’s subtypes and may even lead to a pre-pregnancy screening for Hispanics and others who are likely carriers. Approximately 14 percent of individuals of European ancestry also carry the high-risk gene variation linked to Ph-like ALL.