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

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

Research output: Contribution to journalArticle

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 (Cl), 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% Cl, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4,34; 95% Cl, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% Cl, 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.

Original languageEnglish (US)
Pages (from-to)11592-11597
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number20
DOIs
StatePublished - Sep 25 2001
Externally publishedYes

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Glutathione Transferase
Acute Myeloid Leukemia
Leukemia
Drug Therapy
Odds Ratio
Codon
Alleles
Therapeutics
Radiotherapy
Poisons
Gene Deletion
Carcinogens
Genes
Carcinogenesis
Confidence Intervals
Survival
DNA
Neoplasms

ASJC Scopus subject areas

  • General

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Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. / Allan, James M.; Wild, Christopher P.; Rollinson, Sara; Willett, Eleanor V.; Moorman, Anthony; Dovey, Gareth J.; Roddam, Philippa L.; Roman, Eve; Cartwright, Raymond A.; Morgan, Gareth J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 20, 25.09.2001, p. 11592-11597.

Research output: Contribution to journalArticle

Allan, James M. ; Wild, Christopher P. ; Rollinson, Sara ; Willett, Eleanor V. ; Moorman, Anthony ; Dovey, Gareth J. ; Roddam, Philippa L. ; Roman, Eve ; Cartwright, Raymond A. ; Morgan, Gareth J. / Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 20. pp. 11592-11597.
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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 (Cl), 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{\%} Cl, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4,34; 95{\%} Cl, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95{\%} Cl, 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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T1 - Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

AU - Allan, James M.

AU - Wild, Christopher P.

AU - Rollinson, Sara

AU - Willett, Eleanor V.

AU - Moorman, Anthony

AU - Dovey, Gareth J.

AU - Roddam, Philippa L.

AU - Roman, Eve

AU - Cartwright, Raymond A.

AU - Morgan, Gareth J.

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N2 - 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 (Cl), 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% Cl, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4,34; 95% Cl, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% Cl, 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.

AB - 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 (Cl), 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% Cl, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4,34; 95% Cl, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% Cl, 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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