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Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapyinduced leukemia

Allan, J.M., Wild, C.P., Rollinson, S., Willett, E.V., Moorman, A.V., Dovey, G.J., Roddam, P.L., Roman, E., Cartwright, R.A. and Morgan, G.J. (2001) Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapyinduced leukemia. Proceedings of the National Academy of Sciences, 98 (20). pp. 11592-11597. ISSN 0027-8424

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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.

Item Type: Article
Copyright, Publisher and Additional Information: © Copyright 2001 National Academy of Sciences, U.S.A.
Institution: The University of Leeds
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Oncology and Clinical Research (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Academic Unit of Epidemiology and Health Services Research (Leeds)
Depositing User: Sherpa Assistant
Date Deposited: 13 Mar 2006
Last Modified: 19 Jun 2014 14:04
Published Version: http://www.pnas.org/cgi/reprint/98/20/11592
Status: Published
Refereed: Yes
Identification Number: 10.1073/pnas.191211198
URI: http://eprints.whiterose.ac.uk/id/eprint/575

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