Pharmacogenetics of outcome in children with acute lymphoblastic leukemia.
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.
Rocha
Jose Claudio C
JC
Department of Pharmaceutical Sciences, Saint Jude Children's Research Hospital of the University of Tennessee, Memphis 38105-2794, USA.
Cheng
Cheng
C
Liu
Wei
W
Kishi
Shinji
S
Das
Soma
S
Cook
Edwin H
EH
Sandlund
John T
JT
Rubnitz
Jeffrey
J
Ribeiro
Raul
R
Campana
Dario
D
Pui
Ching-Hon
CH
Evans
William E
WE
Relling
Mary V
MV
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
D000970:Antineoplastic Agents; D005982:Glutathione Transferase; D018167:Receptors, Calcitriol; D013940:Thymidylate Synthase