title: Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia.
abstract: Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11-2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50-2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.
authors.affiliation: Molecular Epidemiology Unit, Academic Unit of Epidemiology and Health Services Research, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom. j.m.allan@leeds.ac.uk
authors.forename: J M
authors.initials: JM
authors.lastname: Allan
authors.forename: C P
authors.initials: CP
authors.lastname: Wild
authors.forename: S
authors.initials: S
authors.lastname: Rollinson
authors.forename: E V
authors.initials: EV
authors.lastname: Willett
authors.forename: A V
authors.initials: AV
authors.lastname: Moorman
authors.forename: G J
authors.initials: GJ
authors.lastname: Dovey
authors.forename: P L
authors.initials: PL
authors.lastname: Roddam
authors.forename: E
authors.initials: E
authors.lastname: Roman
authors.forename: R A
authors.initials: RA
authors.lastname: Cartwright
authors.forename: G J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D007938:Leukemia / Q000139:chemically induced / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology / Q000235:genetics; D011110:Polymorphism, Genetic; D012016:Reference Values; D018570:Risk Assessment
chemical_list: D007527:Isoenzymes; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase