title: Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia.
abstract: The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 × 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 × 10-5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.
authors.affiliation: Comprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA.|Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Karol
authors.affiliation: Department of Pediatrics, Maine Medical Center, Portland, ME, USA.
authors.forename: E
authors.initials: E
authors.lastname: Larsen
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pharmacy Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Fernandez
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: McCorkle
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Paugh
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Autry
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lopez-Lopez
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: B
authors.identifier: 0000-0002-3947-0611
authors.initials: B
authors.lastname: Diouf
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jeha
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Raetz
authors.affiliation: Department of Pediatrics, University of Texas, Southwestern Medical Center, Dallas, TX, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Winick
authors.affiliation: Perlmutter Cancer Center, Department of Pediatrics and Pathology, New York University Langone Medical Center, New York, NY, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Pediatrics, University of California School of Medicine, San Francisco, CA, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000209:etiology; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor