Association ofGATA3Polymorphisms With Minimal Residual Disease and Relapse Risk in Childhood Acute Lymphoblastic Leukemia
Year: 2020
Type: article
Abstract: BACKGROUND: Minimal residual disease (MRD) after induction therapy is one of the strongest prognostic factors in childhood acute lymphoblastic leukemia (ALL), and MRD-directed treatment intensification improves survival. Little is known about the effects of inherited genetic variants on interpatient variability in MRD. METHODS: A genome-wide association study was performed on 2597 children on the Children's Oncology Group AALL0232 trial for high-risk B-cell ALL. Association between genotype and end-of-induction MRD levels was evaluated for 863 370 single nucleotide polymorphisms (SNPs), adjusting for genetic ancestry and treatment strata. Top variants were further evaluated in a validation cohort of 491 patients from the Children's Oncology Group P9905 and 6 ALL trials. The independent prognostic value of single nucleotide polymorphisms was determined in multivariable analyses. All statistical tests were 2-sided. RESULTS: In the discovery genome-wide association study, we identified a genome-wide significant association at the GATA3 locus (rs3824662, odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.35 to 1.84; P = 1.15 × 10-8 as a dichotomous variable). This association was replicated in the validation cohort (P = .003, MRD as a dichotomous variable). The rs3824662 risk allele independently predicted ALL relapse after adjusting for age, white blood cell count, and leukemia DNA index (P = .04 and .007 in the discovery and validation cohort, respectively) and remained prognostic when the analyses were restricted to MRD-negative patients (P = .04 and .03 for the discovery and validation cohorts, respectively). CONCLUSION: Inherited GATA3 variant rs3824662 strongly influences ALL response to remission induction therapy and is associated with relapse. This work highlights the potential utility of germline variants in upfront risk stratification in ALL.
DOI: 10.1093/jnci/djaa138
Authors: Hui Zhang, Anthony Pak-Yin Liu, Meenakshi Devidas, Shawn HR Lee, Xueyuan Cao, Deqing Pei, Michael Borowitz, Brent Wood, Julie M Gastier-Foster, Yunfeng Dai, Elizabeth Raetz, Eric Larsen, Naomi Winick, W Paul Bowman, Seth Karol, Wenjian Yang, Paul L Martin, William L Carroll, Ching-Hon Pui, Charles G Mullighan, William E Evans, Cheng Cheng, Stephen P Hunger, Mary V Relling, Mignon L Loh, Jun J Yang
Institutions: St. Jude Children's Research Hospital, Guangzhou Women and Children Medical Center, University of Florida, National University Health System, University of Tennessee Health Science Center, Johns Hopkins University, Johns Hopkins Medicine, Johns Hopkins Hospital, University of Washington, Nationwide Children's Hospital, The University of Texas Southwestern Medical Center, Cook Children's Medical Center, Duke University, Children's Hospital of Philadelphia, University of Pennsylvania, University of California, San Francisco
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1504112592, G169511485, G2554726104, G2901270230, G2901481919, Pharmacogenomics of Childhood Leukemia ALL, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), G421865639, Children's Oncology Group Statistics and Data Center, G46020690, G4635525836, G5075990039, G6626909389, G865138149, G9000030247, G9000079770, G9000086855, G9000105006, G9000123384, G9000211056, G9000255358, G9000285815, G9000297332, G9000351236, Translating genomic discoveries to improved outcomes for high risk acute leukemia, Cancer Center Support Grant (CCSG), G997771125
OpenAlex ID: W3083876353