title: Pharmacogenetics of outcome in children with acute lymphoblastic leukemia.
abstract: Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) non-null genotype had greater risk of hematologic relapse (P = .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = .02) and intron 8 genotypes (P = .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = .04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy.
authors.affiliation: Department of Pharmaceutical Sciences, Saint Jude Children's Research Hospital of the University of Tennessee, Memphis 38105-2794, USA.
authors.forename: Jose Claudio C
authors.initials: JC
authors.lastname: Rocha
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Shinji
authors.initials: S
authors.lastname: Kishi
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: John T
authors.initials: JT
authors.lastname: Sandlund
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rubnitz
authors.forename: Raul
authors.initials: R
authors.lastname: Ribeiro
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007223:Infant; D007438:Introns; D008954:Models, Biological; D015999:Multivariate Analysis; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D018167:Receptors, Calcitriol / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D012306:Risk; D013940:Thymidylate Synthase / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D005982:Glutathione Transferase; D018167:Receptors, Calcitriol; D013940:Thymidylate Synthase