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

Record type: Article

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.

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Citation

Allan, James M., Wild, Christopher P., Rollinson, Sara, Willett, Eleanor V., Moorman, Anthony V., Dovey, Gareth J., Roddam, Philippa L., Roman, Eve, Cartwright, Raymond A. and Morgan, Gareth J. (2001) Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia Proceedings of the National Academy of Sciences, 98, (20), pp. 11592-11597. (doi:10.1073/pnas.191211198).

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Published date: 2001
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 26188
URI: http://eprints.soton.ac.uk/id/eprint/26188
ISSN: 0027-8424
PURE UUID: 3f24b480-4588-4a2b-bc4f-1f1ceb6bf104

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Date deposited: 24 Apr 2006
Last modified: 17 Jul 2017 16:08

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Contributors

Author: James M. Allan
Author: Christopher P. Wild
Author: Sara Rollinson
Author: Eleanor V. Willett
Author: Anthony V. Moorman
Author: Gareth J. Dovey
Author: Philippa L. Roddam
Author: Eve Roman
Author: Raymond A. Cartwright
Author: Gareth J. Morgan

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