Scientists at St. Jude Children’s Research Hospital are investigating the inherited genetics of childhood leukemia and how particular gene variations can affect treatment outcomes. The research showed that an inherited variation in the GATA3 gene strongly influences early response to chemotherapy and is linked to relapse in children with acute lymphoblastic leukemia (ALL). The work was published as an advance online publication this week in the Journal of the National Cancer Institute.
Minimal residual disease (MRD) checks for the presence of minute numbers of cancer cells after induction therapy, the first stage of ALL treatment. MRD is one of the strongest predictors of relapse risk for young ALL patients.
“We know there is substantial variability in the way patients respond to ALL therapy. Certain mutations in leukemia cells are associated with drug response, but they certainly do not explain the full spectrum of the observed variability. This is when we realize we need to look at inherited genetic variants as well,” said corresponding author Jun J. Yang, Ph.D., of St. Jude Pharmaceutical Sciences and Oncology.
The team conducted a genome-wide association study on children in Children’s Oncology Group clinical trials for high-risk B-ALL. This cohort was large enough for the scientists to look for associations between the inherited genetics and end-of-induction MRD levels for 863,370 single nucleotide polymorphisms.
Results of the study showed that an inherited GATA3 variant strongly influenced how patients responded to therapy. This variant is also associated with relapse. GATA3 is known by scientists to encode a crucial transcription factor for the development and differentiation of T cells.
“This variant isn’t completely new to us; we’ve previously found it to be associated with susceptibility to Philadelphia chromosome-like ALL, a rare but high-risk subtype,” Yang said. “These new findings about the relationship between the GATA3 variant and MRD solidify the potential utility of inherited variants in how we assess newly diagnosed patients for risk-stratified therapy.”
First author of the study is Hui Zhang, M.D., Ph.D., formerly of St. Jude and now of Guangzhou Women and Children's Medical Center. The study’s other St. Jude authors include Mary Relling, Ching-Hon Pui, Charles Mullighan, William Evans, Anthony Pak-Yin Liu, Seth Karol, Wenjian Yang, Deqing Pei and Cheng Cheng. Other authors are Meenakshi Devidas and Yunfeng Dai of the University of Florida, Gainesville; Shawn HR Lee of Khoo Teck Puat-National University Children’s Medical Institute, Singapore; Xueyuan Cao of University of Tennessee Health Science Center; Michael Borowitz of Johns Hopkins Medical Institute; Brent Wood of the University of Washington, Seattle; Julie M. Gastier-Foster of Nationwide Children’s Hospital; Elizabeth Raetz and William Carroll of Stephen D. Hassenfeld Children’s Center for Cancer & Blood Disorders; Eric Larsen of Maine Children’s Cancer Program; Naomi Winick of University of Texas Southwestern Medical Center; W. Paul Bowman of Cook Children's Medical Center; Paul Martin of Duke University; Stephen Hunger of Children’s Hospital of Philadelphia and University of Pennsylvania; and Mignon Loh of Benioff Children’s Hospital and University of California, San Francisco.
The research was funded in part by grants from the National Institutes of Health (CA21765, CA98543, CA114766, CA98413, CA180886, CA180899, GM92666, GM115279 and GM097119); a St. Baldrick’s Foundation International Scholar award; a National Medical Research Council Singapore Research Training Fellowship; and ALSAC, the fundraising and awareness organization of St. Jude.
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