Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia

Sook Wah Yee, Joel A. Mefford, Natasha Singh, Mary Elizabeth Percival, Adrian Stecula, Kuo Yang, John S. Witte, Atsushi Takahashi, Michiaki Kubo, Koichi Matsuda, Kathleen M. Giacomini, Charalambos Andreadis

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Abstract

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10-6) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.

Original languageEnglish
Pages (from-to)353-361
Number of pages9
JournalJournal of Human Genetics
Volume58
Issue number6
DOIs
Publication statusPublished - 01-06-2013

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Acute Myeloid Leukemia
Disease-Free Survival
Pharmaceutical Preparations
Genes
Stem Cell Transplantation
Single Nucleotide Polymorphism
Busulfan
Cytarabine
Etoposide
Proportional Hazards Models
Pharmacokinetics
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Yee, S. W., Mefford, J. A., Singh, N., Percival, M. E., Stecula, A., Yang, K., ... Andreadis, C. (2013). Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia. Journal of Human Genetics, 58(6), 353-361. https://doi.org/10.1038/jhg.2013.38
Yee, Sook Wah ; Mefford, Joel A. ; Singh, Natasha ; Percival, Mary Elizabeth ; Stecula, Adrian ; Yang, Kuo ; Witte, John S. ; Takahashi, Atsushi ; Kubo, Michiaki ; Matsuda, Koichi ; Giacomini, Kathleen M. ; Andreadis, Charalambos. / Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia. In: Journal of Human Genetics. 2013 ; Vol. 58, No. 6. pp. 353-361.
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abstract = "Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10{\%} to over 70{\%} for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10-6) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.",
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Yee, SW, Mefford, JA, Singh, N, Percival, ME, Stecula, A, Yang, K, Witte, JS, Takahashi, A, Kubo, M, Matsuda, K, Giacomini, KM & Andreadis, C 2013, 'Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia', Journal of Human Genetics, vol. 58, no. 6, pp. 353-361. https://doi.org/10.1038/jhg.2013.38

Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia. / Yee, Sook Wah; Mefford, Joel A.; Singh, Natasha; Percival, Mary Elizabeth; Stecula, Adrian; Yang, Kuo; Witte, John S.; Takahashi, Atsushi; Kubo, Michiaki; Matsuda, Koichi; Giacomini, Kathleen M.; Andreadis, Charalambos.

In: Journal of Human Genetics, Vol. 58, No. 6, 01.06.2013, p. 353-361.

Research output: Contribution to journalArticle

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AU - Yee, Sook Wah

AU - Mefford, Joel A.

AU - Singh, Natasha

AU - Percival, Mary Elizabeth

AU - Stecula, Adrian

AU - Yang, Kuo

AU - Witte, John S.

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Matsuda, Koichi

AU - Giacomini, Kathleen M.

AU - Andreadis, Charalambos

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N2 - Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10-6) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.

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