Association of CYP3A4 genotype with treatment-related leukemia

Carolyn A. Felix, Amy H. Walker, Beverly J. Lange, Terence M. Williams, Naomi J. Winick, Nai Kong V Cheung, Brian D. Lovett, Peter C. Nowell, Ian A. Blair, Timothy R. Rebbeck

Research output: Contribution to journalArticle

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Abstract

Epipodophyliotoxins are associated with leukemias characterized by translocations of the MLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodopbyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5' promoter region of the CYP3A4 gene (CYP3A4-V) that might alter the metabolism of anticancer drugs. We examined 99 de novo and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V (P = 0.026; Fisher's Exact Test, FET). Nine of 42 de novo leukemias with MLL gene translocations (21%), and 0 of 22 treatment- related leukemias with MLL gene translocations carried the CYP3A4-V (P = 0.016, FET). This relationship remained significant when 19 treatment- related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases (P = 0.026, FET). These data suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The CYP3A4. W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.

Original languageEnglish (US)
Pages (from-to)13176-13181
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number22
DOIs
StatePublished - Oct 27 1998

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Cytochrome P-450 CYP3A
Leukemia
Genotype
Podophyllotoxin
Genes
DNA
Genetic Promoter Regions
Pharmaceutical Preparations
DNA Damage
Electrophoresis
Chromosomes
Gels

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Association of CYP3A4 genotype with treatment-related leukemia. / Felix, Carolyn A.; Walker, Amy H.; Lange, Beverly J.; Williams, Terence M.; Winick, Naomi J.; Cheung, Nai Kong V; Lovett, Brian D.; Nowell, Peter C.; Blair, Ian A.; Rebbeck, Timothy R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 22, 27.10.1998, p. 13176-13181.

Research output: Contribution to journalArticle

Felix, CA, Walker, AH, Lange, BJ, Williams, TM, Winick, NJ, Cheung, NKV, Lovett, BD, Nowell, PC, Blair, IA & Rebbeck, TR 1998, 'Association of CYP3A4 genotype with treatment-related leukemia', Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 22, pp. 13176-13181. https://doi.org/10.1073/pnas.95.22.13176
Felix, Carolyn A. ; Walker, Amy H. ; Lange, Beverly J. ; Williams, Terence M. ; Winick, Naomi J. ; Cheung, Nai Kong V ; Lovett, Brian D. ; Nowell, Peter C. ; Blair, Ian A. ; Rebbeck, Timothy R. / Association of CYP3A4 genotype with treatment-related leukemia. In: Proceedings of the National Academy of Sciences of the United States of America. 1998 ; Vol. 95, No. 22. pp. 13176-13181.
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abstract = "Epipodophyliotoxins are associated with leukemias characterized by translocations of the MLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodopbyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5' promoter region of the CYP3A4 gene (CYP3A4-V) that might alter the metabolism of anticancer drugs. We examined 99 de novo and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19{\%}) and 1 of 30 treatment-related (3{\%}) leukemias carried the CYP3A4-V (P = 0.026; Fisher's Exact Test, FET). Nine of 42 de novo leukemias with MLL gene translocations (21{\%}), and 0 of 22 treatment- related leukemias with MLL gene translocations carried the CYP3A4-V (P = 0.016, FET). This relationship remained significant when 19 treatment- related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases (P = 0.026, FET). These data suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The CYP3A4. W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.",
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AU - Felix, Carolyn A.

AU - Walker, Amy H.

AU - Lange, Beverly J.

AU - Williams, Terence M.

AU - Winick, Naomi J.

AU - Cheung, Nai Kong V

AU - Lovett, Brian D.

AU - Nowell, Peter C.

AU - Blair, Ian A.

AU - Rebbeck, Timothy R.

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N2 - Epipodophyliotoxins are associated with leukemias characterized by translocations of the MLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodopbyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5' promoter region of the CYP3A4 gene (CYP3A4-V) that might alter the metabolism of anticancer drugs. We examined 99 de novo and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V (P = 0.026; Fisher's Exact Test, FET). Nine of 42 de novo leukemias with MLL gene translocations (21%), and 0 of 22 treatment- related leukemias with MLL gene translocations carried the CYP3A4-V (P = 0.016, FET). This relationship remained significant when 19 treatment- related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases (P = 0.026, FET). These data suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The CYP3A4. W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.

AB - Epipodophyliotoxins are associated with leukemias characterized by translocations of the MLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodopbyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5' promoter region of the CYP3A4 gene (CYP3A4-V) that might alter the metabolism of anticancer drugs. We examined 99 de novo and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V (P = 0.026; Fisher's Exact Test, FET). Nine of 42 de novo leukemias with MLL gene translocations (21%), and 0 of 22 treatment- related leukemias with MLL gene translocations carried the CYP3A4-V (P = 0.016, FET). This relationship remained significant when 19 treatment- related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases (P = 0.026, FET). These data suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The CYP3A4. W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.

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