A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy

Kazuma Kiyotani, Satoko Uno, Taisei Mushiroda, Atsushi Takahashi, Michiaki Kubo, Naoki Mitsuhata, Shinomi Ina, Chikashi Kihara, Yasutoshi Kimura, Hiroki Yamaue, Koichi Hirata, Yusuke Nakamura, Hitoshi Zembutsu

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: Genetic factors are thought to be one of the causes of individual variability in the adverse reactions observed in cancer patients who received gemcitabine therapy. However, genetic factors determining the risk of adverse reactions of gemcitabine are not fully understood. PATIENTS AND METHODS: To identify a genetic factor(s) determining the risk of gemcitabine-induced leukopenia/neutropenia, we conducted a genome-wide association study, by genotyping over 610 000 single nucleotide polymorphisms (SNPs), and a replication study in a total of 174 patients, including 54 patients with at least grade 3 leukopenia/neutropenia and 120 patients without any toxicities. RESULTS: We identified four loci possibly associated with gemcitabine-induced leukopenia/neutropenia [rs11141915 in DAPK1 on chromosome 9q21, combined P=1.27×10, odds ratio (OR)=4.10; rs1901440 on chromosome 2q12, combined P=3.11×10, OR=34.00; rs12046844 in PDE4B on chromosome 1p31, combined P=4.56×10, OR=4.13; rs11719165 on chromosome 3q29, combined P=5.98×10, OR=2.60]. When we examined the combined effects of these four SNPs, by classifying patients into four groups on the basis of the total number of risk genotypes of these four SNPs, significantly higher risks of gemcitabine-induced leukopenia/neutropenia were observed in the patients having two and three risk genotypes (P=6.25×10, OR=11.97 and P=4.13×10, OR=50.00, respectively) relative to patients with zero or one risk genotype. CONCLUSION: We identified four novel SNPs associated with gemcitabine-induced severe leukopenia/neutropenia. These SNPs might be applicable in predicting the risk of hematological toxicity in patients receiving gemcitabine therapy.

Original languageEnglish
Pages (from-to)229-235
Number of pages7
JournalPharmacogenetics and Genomics
Volume22
Issue number4
DOIs
Publication statusPublished - 01-04-2012
Externally publishedYes

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gemcitabine
Genome-Wide Association Study
Genetic Markers
Leukopenia
Neutropenia
Odds Ratio
Single Nucleotide Polymorphism
Neoplasms
Chromosomes
Genotype
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kiyotani, Kazuma ; Uno, Satoko ; Mushiroda, Taisei ; Takahashi, Atsushi ; Kubo, Michiaki ; Mitsuhata, Naoki ; Ina, Shinomi ; Kihara, Chikashi ; Kimura, Yasutoshi ; Yamaue, Hiroki ; Hirata, Koichi ; Nakamura, Yusuke ; Zembutsu, Hitoshi. / A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy. In: Pharmacogenetics and Genomics. 2012 ; Vol. 22, No. 4. pp. 229-235.
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title = "A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy",
abstract = "OBJECTIVE: Genetic factors are thought to be one of the causes of individual variability in the adverse reactions observed in cancer patients who received gemcitabine therapy. However, genetic factors determining the risk of adverse reactions of gemcitabine are not fully understood. PATIENTS AND METHODS: To identify a genetic factor(s) determining the risk of gemcitabine-induced leukopenia/neutropenia, we conducted a genome-wide association study, by genotyping over 610 000 single nucleotide polymorphisms (SNPs), and a replication study in a total of 174 patients, including 54 patients with at least grade 3 leukopenia/neutropenia and 120 patients without any toxicities. RESULTS: We identified four loci possibly associated with gemcitabine-induced leukopenia/neutropenia [rs11141915 in DAPK1 on chromosome 9q21, combined P=1.27×10, odds ratio (OR)=4.10; rs1901440 on chromosome 2q12, combined P=3.11×10, OR=34.00; rs12046844 in PDE4B on chromosome 1p31, combined P=4.56×10, OR=4.13; rs11719165 on chromosome 3q29, combined P=5.98×10, OR=2.60]. When we examined the combined effects of these four SNPs, by classifying patients into four groups on the basis of the total number of risk genotypes of these four SNPs, significantly higher risks of gemcitabine-induced leukopenia/neutropenia were observed in the patients having two and three risk genotypes (P=6.25×10, OR=11.97 and P=4.13×10, OR=50.00, respectively) relative to patients with zero or one risk genotype. CONCLUSION: We identified four novel SNPs associated with gemcitabine-induced severe leukopenia/neutropenia. These SNPs might be applicable in predicting the risk of hematological toxicity in patients receiving gemcitabine therapy.",
author = "Kazuma Kiyotani and Satoko Uno and Taisei Mushiroda and Atsushi Takahashi and Michiaki Kubo and Naoki Mitsuhata and Shinomi Ina and Chikashi Kihara and Yasutoshi Kimura and Hiroki Yamaue and Koichi Hirata and Yusuke Nakamura and Hitoshi Zembutsu",
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Kiyotani, K, Uno, S, Mushiroda, T, Takahashi, A, Kubo, M, Mitsuhata, N, Ina, S, Kihara, C, Kimura, Y, Yamaue, H, Hirata, K, Nakamura, Y & Zembutsu, H 2012, 'A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy', Pharmacogenetics and Genomics, vol. 22, no. 4, pp. 229-235. https://doi.org/10.1097/FPC.0b013e32834e9eba

A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy. / Kiyotani, Kazuma; Uno, Satoko; Mushiroda, Taisei; Takahashi, Atsushi; Kubo, Michiaki; Mitsuhata, Naoki; Ina, Shinomi; Kihara, Chikashi; Kimura, Yasutoshi; Yamaue, Hiroki; Hirata, Koichi; Nakamura, Yusuke; Zembutsu, Hitoshi.

In: Pharmacogenetics and Genomics, Vol. 22, No. 4, 01.04.2012, p. 229-235.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy

AU - Kiyotani, Kazuma

AU - Uno, Satoko

AU - Mushiroda, Taisei

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Mitsuhata, Naoki

AU - Ina, Shinomi

AU - Kihara, Chikashi

AU - Kimura, Yasutoshi

AU - Yamaue, Hiroki

AU - Hirata, Koichi

AU - Nakamura, Yusuke

AU - Zembutsu, Hitoshi

PY - 2012/4/1

Y1 - 2012/4/1

N2 - OBJECTIVE: Genetic factors are thought to be one of the causes of individual variability in the adverse reactions observed in cancer patients who received gemcitabine therapy. However, genetic factors determining the risk of adverse reactions of gemcitabine are not fully understood. PATIENTS AND METHODS: To identify a genetic factor(s) determining the risk of gemcitabine-induced leukopenia/neutropenia, we conducted a genome-wide association study, by genotyping over 610 000 single nucleotide polymorphisms (SNPs), and a replication study in a total of 174 patients, including 54 patients with at least grade 3 leukopenia/neutropenia and 120 patients without any toxicities. RESULTS: We identified four loci possibly associated with gemcitabine-induced leukopenia/neutropenia [rs11141915 in DAPK1 on chromosome 9q21, combined P=1.27×10, odds ratio (OR)=4.10; rs1901440 on chromosome 2q12, combined P=3.11×10, OR=34.00; rs12046844 in PDE4B on chromosome 1p31, combined P=4.56×10, OR=4.13; rs11719165 on chromosome 3q29, combined P=5.98×10, OR=2.60]. When we examined the combined effects of these four SNPs, by classifying patients into four groups on the basis of the total number of risk genotypes of these four SNPs, significantly higher risks of gemcitabine-induced leukopenia/neutropenia were observed in the patients having two and three risk genotypes (P=6.25×10, OR=11.97 and P=4.13×10, OR=50.00, respectively) relative to patients with zero or one risk genotype. CONCLUSION: We identified four novel SNPs associated with gemcitabine-induced severe leukopenia/neutropenia. These SNPs might be applicable in predicting the risk of hematological toxicity in patients receiving gemcitabine therapy.

AB - OBJECTIVE: Genetic factors are thought to be one of the causes of individual variability in the adverse reactions observed in cancer patients who received gemcitabine therapy. However, genetic factors determining the risk of adverse reactions of gemcitabine are not fully understood. PATIENTS AND METHODS: To identify a genetic factor(s) determining the risk of gemcitabine-induced leukopenia/neutropenia, we conducted a genome-wide association study, by genotyping over 610 000 single nucleotide polymorphisms (SNPs), and a replication study in a total of 174 patients, including 54 patients with at least grade 3 leukopenia/neutropenia and 120 patients without any toxicities. RESULTS: We identified four loci possibly associated with gemcitabine-induced leukopenia/neutropenia [rs11141915 in DAPK1 on chromosome 9q21, combined P=1.27×10, odds ratio (OR)=4.10; rs1901440 on chromosome 2q12, combined P=3.11×10, OR=34.00; rs12046844 in PDE4B on chromosome 1p31, combined P=4.56×10, OR=4.13; rs11719165 on chromosome 3q29, combined P=5.98×10, OR=2.60]. When we examined the combined effects of these four SNPs, by classifying patients into four groups on the basis of the total number of risk genotypes of these four SNPs, significantly higher risks of gemcitabine-induced leukopenia/neutropenia were observed in the patients having two and three risk genotypes (P=6.25×10, OR=11.97 and P=4.13×10, OR=50.00, respectively) relative to patients with zero or one risk genotype. CONCLUSION: We identified four novel SNPs associated with gemcitabine-induced severe leukopenia/neutropenia. These SNPs might be applicable in predicting the risk of hematological toxicity in patients receiving gemcitabine therapy.

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U2 - 10.1097/FPC.0b013e32834e9eba

DO - 10.1097/FPC.0b013e32834e9eba

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EP - 235

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

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