title: Glutathione S-transferase genotypes in children who develop treatment-related acute myeloid malignancies.
abstract: Epipodophyllotoxin-associated secondary myeloid leukemia is a devastating complication of acute lymphoblastic leukemia (ALL) therapy. The risk factors for treatment-related myeloid leukemia remain incompletely defined. Genetic deficiencies in glutathione S-transferase (GST) activities have been linked to higher frequencies of a number of human malignancies. Our objective was to determine whether the null genotype for GSTM1, GSTT1, or both, was more frequent in children with ALL who developed treatment-related myeloid malignancies as compared to those who did not. A PCR technique was used to assay for the null genotype for GSTM1 and GSTT1 in 302 children with ALL, 57 of whom also subsequently developed treatment-related acute myeloid leukemia or myelodysplastic syndrome. Among children with ALL who did not develop treatment-related myeloid malignancies, the frequencies of GSTM1 and GSTT1 wild-type, GSTM1 null-GSTT1 wild-type, GSTM1 wild-type-GSTT1 null, and GSTM1 and GSTT1 null genotypes were 40%, 42%, 9% and 9%, respectively. The corresponding frequencies for patients who developed acute myeloid malignancies were 42%, 32%, 11% and 16%, respectively (P = 0.26). A statistically significant increase in the frequency of the GST null genotype was observed in male patients who developed myeloid malignancies as compared to male ALL control patients (P = 0.036), but was not observed in female patients (P = 0.51). Moreover, a logistic regression analysis of possible predictors for myeloid malignancies, controlling for gender and race, did not reveal an association of GSTM1 or GSTT1 null genotypes (P = 0.62 and 0.11, respectively) with treatment-related malignancies. Our data suggest that GSTM1 and GSTT1 null genotypes may not predispose to epipodophyllotoxin-associated myeloid malignancies.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Woo
authors.forename: J J
authors.initials: JJ
authors.lastname: Shuster
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: R O
authors.initials: RO
authors.lastname: Bash
authors.forename: F G
authors.initials: FG
authors.lastname: Behm
authors.forename: B
authors.initials: B
authors.lastname: Camitta
authors.forename: C A
authors.initials: CA
authors.lastname: Felix
authors.forename: B A
authors.initials: BA
authors.lastname: Kamen
authors.forename: C H
authors.initials: CH
authors.lastname: Pui
authors.forename: S C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: N J
authors.initials: NJ
authors.lastname: Winick
authors.forename: M D
authors.initials: MD
authors.lastname: Amylon
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics; D008297:Male; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics; D011034:Podophyllotoxin / Q000009:adverse effects* / Q000627:therapeutic use; D016133:Polymerase Chain Reaction / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D012307:Risk Factors; D014481:United States
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D005982:Glutathione Transferase; D011034:Podophyllotoxin