Hui Zhang1,2, Anthony Pak-Yin Liu3, Meenakshi Devidas4,5, Shawn Hr Lee1,6, Xueyuan Cao7, Deqing Pei8, Michael Borowitz9, Brent Wood10, Julie M Gastier-Foster11, Yunfeng Dai5, Elizabeth Raetz12, Eric Larsen13, Naomi Winick14, W Paul Bowman15, Seth Karol3, Wenjian Yang1, Paul L Martin16, William L Carroll12, Ching-Hon Pui3, Charles G Mullighan17, William E Evans1, Cheng Cheng8, Stephen P Hunger18, Mary V Relling1, Mignon L Loh19, Jun J Yang1. 1. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA. 2. Department of Hematology & Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, China. 3. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA. 4. Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN, USA. 5. Department of Biostatistics, University of Florida, Gainesville, FL, USA. 6. Division of Paediatric Hematology-Oncology, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore. 7. Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA. 8. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA. 9. Division of Hematologic Pathology, Department of Pathology, Johns Hopkins Medical Institute, Baltimore, MD, USA. 10. Department of Laboratory Medicine, University of Washington, Seattle, WA, USA. 11. Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. 12. Division of Pediatric Hematology/Oncology, Department of Pediatrics, Stephen D. Hassenfeld Children's Center for Cancer & Blood Disorders, New York, NY, USA. 13. Maine Children's Cancer Program, Scarborough, ME, USA. 14. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. 15. Department of Pediatrics, Cook Children's Medical Center, Fort Worth, TX, USA. 16. Department of Pediatrics, Duke University, Durham, NC, USA. 17. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA. 18. Division of Oncology and the Center for Childhood Cancer Research, Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. 19. Division of Hematology Oncology, Department of Pediatrics, Benioff Children's Hospital and University of California, San Francisco, San Francisco, CA, USA.
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.
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.
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