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

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with 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 2-step...

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Main Authors:	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
Format:	Online
Language:	English
Published:	2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068832/

id	pubmed-4068832
recordtype	oai_dc
spelling	pubmed-40688322014-06-24 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 Article Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with 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 2-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. 154 genetically European patients were used for the primary analysis. An intronic SNP in ABCC3 (rs4148405) was associated with a significantly shorter DFS (HR=3.2, p=5.6 x 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. 2013-05-16 2013-06 /pmc/articles/PMC4068832/ /pubmed/23677058 http://dx.doi.org/10.1038/jhg.2013.38 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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
spellingShingle	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
author_facet	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
author_sort	Yee, Sook Wah
title	Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia
title_short	Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia
title_full	Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia
title_fullStr	Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia
title_full_unstemmed	Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia
title_sort	impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia
description	Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with 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 2-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. 154 genetically European patients were used for the primary analysis. An intronic SNP in ABCC3 (rs4148405) was associated with a significantly shorter DFS (HR=3.2, p=5.6 x 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.
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068832/
_version_	1612105395233357824

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

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