Association of GATA3 Polymorphisms With Minimal Residual Disease and Relapse Risk in Childhood Acute Lymphoblastic Leukemia

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. MullighanWilliam E. Evans, Cheng Cheng, Stephen P. Hunger, Mary V. Relling, Mignon L. Loh, Jun J. Yang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)408-417
Number of pages10
JournalJournal of the National Cancer Institute
Volume113
Issue number4
DOIs
StatePublished - Apr 6 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Association of GATA3 Polymorphisms With Minimal Residual Disease and Relapse Risk in Childhood Acute Lymphoblastic Leukemia'. Together they form a unique fingerprint.

Cite this