title: Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia.
abstract: BACKGROUND
  Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response.
  
  
  OBJECTIVE
  To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy.
  
  
  METHODS
  Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006.
  
  
  METHODS
  Minimal residual disease at the end of induction therapy, measured by flow cytometry.
  
  
  RESULTS
  There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition.
  
  
  CONCLUSIONS
  Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Cao
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Pounds
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Treviño
authors.forename: Deborah
authors.initials: D
authors.lastname: French
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: W P
authors.initials: WP
authors.lastname: Bowman
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Camitta
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D016014:Linear Models; D015810:Linkage Disequilibrium; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D018365:Neoplasm, Residual / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D005047:Etoposide; D008727:Methotrexate