Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan

Siew Kee Low, Suyoun Chung, Atsushi Takahashi, Hitoshi Zembutsu, Taisei Mushiroda, Michiaki Kubo, Yusuke Nakamura

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Chemotherapeutic agents are notoriously known to have a narrow therapeutic range that often results in life-threatening toxicity. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy through a pharmacogenomics approach. In this study, we carried out multiple genome-wide association studies (GWAS) of 13 122 cancer patients who received different chemotherapy regimens, including cyclophosphamide- and platinum-based (cisplatin and carboplatin), anthracycline-based (doxorubicin and epirubicin), and antimetabolite-based (5-fluorouracil and gemcitabine) treatment, antimicrotubule agents (paclitaxel and docetaxel), and topoisomerase inhibitors (camptothecin and etoposide), as well as combination therapy with paclitaxel and carboplatin, to identify genetic variants that are associated with the risk of severe neutropenia/leucopenia in the Japanese population. In addition, we used a weighted genetic risk scoring system to evaluate the cumulative effects of the suggestive genetic variants identified from GWAS in order to predict the risk levels of individuals who carry multiple risk alleles. Although we failed to identify genetic variants that surpassed the genome-wide significance level (P < 5.0 × 10-8) through GWAS, probably due to insufficient statistical power and complex clinical features, we were able to shortlist some of the suggestive associated loci. The current study is at the relatively preliminary stage, but does highlight the complexity and problematic issues associated with retrospective pharmacogenomics studies. However, we hope that verification of these genetic variants through local and international collaborations could improve the clinical outcome for cancer patients.

Original languageEnglish
Pages (from-to)1074-1082
Number of pages9
JournalCancer Science
Volume104
Issue number8
DOIs
Publication statusPublished - 01-01-2013
Externally publishedYes

Fingerprint

Genome-Wide Association Study
Leukopenia
Neutropenia
Japan
Carboplatin
docetaxel
gemcitabine
Paclitaxel
Topoisomerase Inhibitors
Antimetabolites
Drug Therapy
Camptothecin
Epirubicin
Pharmacogenetics
Anthracyclines
Etoposide
Platinum
Fluorouracil
Doxorubicin
Cyclophosphamide

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Low, Siew Kee ; Chung, Suyoun ; Takahashi, Atsushi ; Zembutsu, Hitoshi ; Mushiroda, Taisei ; Kubo, Michiaki ; Nakamura, Yusuke. / Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. In: Cancer Science. 2013 ; Vol. 104, No. 8. pp. 1074-1082.
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Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. / Low, Siew Kee; Chung, Suyoun; Takahashi, Atsushi; Zembutsu, Hitoshi; Mushiroda, Taisei; Kubo, Michiaki; Nakamura, Yusuke.

In: Cancer Science, Vol. 104, No. 8, 01.01.2013, p. 1074-1082.

Research output: Contribution to journalArticle

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AU - Mushiroda, Taisei

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AU - Nakamura, Yusuke

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